International Journal of Molecular Sciences

Editorial

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4 pages, 196 KiB

Open AccessEditorial

Cardiovascular Diseases—A Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies

by Łukasz Bułdak

Int. J. Mol. Sci. 2022, 23(9), 4695; https://doi.org/10.3390/ijms23094695 - 23 Apr 2022

Cited by 6 | Viewed by 2866

Abstract

Long-term consequences of atherosclerosis remain the major culprit of mortality in developed and developing countries [...] Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

Research

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16 pages, 2279 KiB

Open AccessArticle

The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia

by Hwa Young Song, Jee-In Chung, Angela Melinda Anthony Jalin, Chung Ju, Kisoo Pahk, Chanmin Joung, Sekwang Lee, Sejong Jin, Byoung Soo Kim, Ki Sung Lee, Jei-Man Ryu and Won-Ki Kim

Int. J. Mol. Sci. 2022, 23(3), 1403; https://doi.org/10.3390/ijms23031403 - 26 Jan 2022

Cited by 4 | Viewed by 4524

Abstract

Acute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke [...] Read more.

Acute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke onset) exacerbates ischemic brain damage by causing intracerebral hemorrhage and increasing neurotoxicity. In the present study, we investigated whether the neuroprotant otaplimastat reduced delayed rtPA treatment-evoked neurotoxicity in male Sprague Dawley rats subjected to embolic middle cerebral artery occlusion (eMCAO). Otaplimastat reduced cerebral infarct size and edema and improved neurobehavioral deficits. In particular, otaplimastat markedly reduced intracerebral hemorrhagic transformation and mortality triggered by delayed rtPA treatment, consequently extending the therapeutic time window of rtPA. We further found that ischemia-evoked extracellular matrix metalloproteases (MMPs) expression was closely correlated with cerebral hemorrhagic transformation and brain damage. In ischemic conditions, delayed rtPA treatment further increased brain injury via synergistic expression of MMPs in vascular endothelial cells. In oxygen-glucose-deprived endothelial cells, otaplimastat suppressed the activity rather than protein expression of MMPs by restoring the level of tissue inhibitor of metalloproteinase (TIMP) suppressed in ischemia, and consequently reduced vascular permeation. This paper shows that otaplimastat under clinical trials is a new drug which can inhibit stroke on its own and extend the therapeutic time window of rtPA, especially when administered in combination with rtPA. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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15 pages, 4437 KiB

Open AccessArticle

A Systematic Approach to Assess the Activity and Classification of PCSK9 Variants

by Kepa B. Uribe, Kevin Chemello, Asier Larrea-Sebal, Asier Benito-Vicente, Unai Galicia-Garcia, Steeve Bourane, Ali K. Jaafar, Gilles Lambert and César Martín

Int. J. Mol. Sci. 2021, 22(24), 13602; https://doi.org/10.3390/ijms222413602 - 18 Dec 2021

Cited by 10 | Viewed by 2732

Abstract

Background: Gain of function (GOF) mutations of PCSK9 cause autosomal dominant familial hypercholesterolemia as they reduce the abundance of LDL receptor (LDLR) more efficiently than wild-type PCSK9. In contrast, PCSK9 loss of function (LOF) variants are associated with a hypocholesterolemic phenotype. Dozens of [...] Read more.

Background: Gain of function (GOF) mutations of PCSK9 cause autosomal dominant familial hypercholesterolemia as they reduce the abundance of LDL receptor (LDLR) more efficiently than wild-type PCSK9. In contrast, PCSK9 loss of function (LOF) variants are associated with a hypocholesterolemic phenotype. Dozens of PCSK9 variants have been reported, but most remain of unknown significance since their characterization has not been conducted. Objective: Our aim was to make the most comprehensive assessment of PCSK9 variants and to determine the simplest approach for the classification of these variants. Methods: The expression, maturation, secretion, and activity of nine well-established PCSK9 variants were assessed in transiently transfected HEK293 cells by Western blot and flow cytometry. Their extracellular activities were determined in HepG2 cells incubated with the purified recombinant PCSK9 variants. Their binding affinities toward the LDLR were determined by solid-phase immunoassay. Results: LDLR expression increased when cells were transfected with LOF variants and reduced when cells were transfected with GOF variants compared with wild-type PCSK9. Extracellular activities measurements yielded exactly similar results. GOF and LOF variants had increased, respectively reduced, affinities for the LDLR compared with wild-type PCSK9 with the exception of one GOF variant (R218S) that showed complete resistance to inactivation by furin. All variants were expressed at similar levels and underwent normal maturation and secretion patterns except for two LOF and two GOF mutants. Conclusions: We propose that transient transfections of HEK293 cells with a plasmid encoding a PCSK9 variant followed by LDLR expression assessment by flow cytometry is sufficient to reliably determine its GOF or LOF status. More refined experiments should only be used to determine the underlying mechanism(s) at hand. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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13 pages, 3521 KiB

Open AccessArticle

Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio

by Anna Wiśniewska, Aneta Stachowicz, Katarzyna Kuś, Magdalena Ulatowska-Białas, Justyna Totoń-Żurańska, Anna Kiepura, Kamila Stachyra, Maciej Suski, Mariusz Gajda, Jacek Jawień and Rafał Olszanecki

Int. J. Mol. Sci. 2021, 22(19), 10688; https://doi.org/10.3390/ijms221910688 - 01 Oct 2021

Cited by 10 | Viewed by 2977

Abstract

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can [...] Read more.

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE^−/− mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE^−/− mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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23 pages, 6049 KiB

Open AccessArticle

Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress

by Jaroslava Trnovska, Petr Svoboda, Helena Pelantova, Marek Kuzma, Helena Kratochvilova, Barbora Judita Kasperova, Iveta Dvorakova, Katerina Rosolova, Hana Malinska, Martina Huttl, Irena Markova, Olena Oliyarnyk, Magdalena Melcova, Vojtech Skop, Milos Mraz, Sona Stemberkova-Hubackova and Martin Haluzik

Int. J. Mol. Sci. 2021, 22(19), 10606; https://doi.org/10.3390/ijms221910606 - 30 Sep 2021

Cited by 12 | Viewed by 4408

Abstract

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model [...] Read more.

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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Graphical abstract

8 pages, 957 KiB

Open AccessCommunication

Local Preirradiation of Infarcted Cardiac Tissue Substantially Enhances Cell Engraftment

by Gloria Abizanda, Leyre López-Muneta, Javier Linares, Luis I. Ramos, Arantxa Baraibar-Churio, Miriam Bobadilla, Elena Iglesias, Giulia Coppiello, Purificación Ripalda-Cemboráin, Xabier L. Aranguren, Felipe Prósper, Ana Pérez-Ruiz and Xonia Carvajal-Vergara

Int. J. Mol. Sci. 2021, 22(17), 9126; https://doi.org/10.3390/ijms22179126 - 24 Aug 2021

Cited by 1 | Viewed by 1450

Abstract

The success of cell therapy for the treatment of myocardial infarction depends on finding novel approaches that can substantially implement the engraftment of the transplanted cells. In order to enhance cell engraftment, most studies have focused on the pretreatment of transplantable cells. Here [...] Read more.

The success of cell therapy for the treatment of myocardial infarction depends on finding novel approaches that can substantially implement the engraftment of the transplanted cells. In order to enhance cell engraftment, most studies have focused on the pretreatment of transplantable cells. Here we have considered an alternative approach that involves the preconditioning of infarcted heart tissue to reduce endogenous cell activity and thus provide an advantage to our exogenous cells. This treatment is routinely used in other tissues such as bone marrow and skeletal muscle to improve cell engraftment, but it has never been taken in cardiac tissue. To avoid long-term cardiotoxicity induced by full heart irradiation we developed a rat model of a catheter-based heart irradiation system to locally impact a delimited region of the infarcted cardiac tissue. As proof of concept, we transferred ZsGreen⁺iPSCs in the infarcted heart, due to their ease of use and detection. We found a very significant increase in cell engraftment in preirradiated rats. In this study, we demonstrate for the first time that preconditioning the infarcted cardiac tissue with local irradiation can substantially enhance cell engraftment. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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16 pages, 4007 KiB

Open AccessArticle

Effect of Neprilysin Inhibition for Ischemic Mitral Regurgitation after Myocardial Injury

by Sahmin Lee, Hyo-Sook Hwang, Naaleum Song, Geun-Hyung Kang, Kyoung-Hee Choi, Eunhye Ji, Jong-Min Song and Duk-Hyun Kang

Int. J. Mol. Sci. 2021, 22(16), 8598; https://doi.org/10.3390/ijms22168598 - 10 Aug 2021

Cited by 2 | Viewed by 2591

Abstract

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional [...] Read more.

Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-β and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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12 pages, 17045 KiB

Open AccessArticle

Vitamin D Deficiency and Gender Alter Vasoconstrictor and Vasodilator Reactivity in Rat Carotid Artery

by Miklós Sipos, Dóra Gerszi, Hicham Dalloul, Bálint Bányai, Réka Eszter Sziva, Réka Kollarics, Péter Magyar, Marianna Török, Nándor Ács, Mária Szekeres, György L. Nádasy, Leila Hadjadj, Eszter Mária Horváth and Szabolcs Várbíró

Int. J. Mol. Sci. 2021, 22(15), 8029; https://doi.org/10.3390/ijms22158029 - 27 Jul 2021

Cited by 5 | Viewed by 2103

Abstract

The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of [...] Read more.

The vitamin-D-sensitivity of the cardiovascular system may show gender differences. The prevalence of vitamin D (VD) deficiency (VDD) is high, and it alters cardiovascular function and increases the risk of stroke. Our aim was to investigate the vascular reactivity and histological changes of isolated carotid artery of female and male rats in response to different VD supplies. A total of 48 male and female Wistar rats were divided into four groups: female VD supplemented, female VDD, male VD supplemented, male VDD. The vascular function of isolated carotid artery segments was examined by wire myography. Both vitamin D deficiency and male gender resulted in increased phenylephrine-induced contraction. Acetylcholine-induced relaxation decreased in male rats independently from VD status. Inhibition of prostanoid signaling by indomethacin reduced contraction in females, but increased relaxation ability in male rats. Functional changes were accompanied by VDD and gender-specific histological alterations. Elastic fiber density was significantly decreased by VDD in female rats, but not in males. Smooth muscle actin and endothelial nitric oxide synthase levels were significantly lowered, but the thromboxane receptor was elevated in VDD males. Decreased nitrative stress was detected in both male groups independently from VD supply. The observed interactions between vitamin D deficiency and sex may play a role in the gender difference of cardiovascular risk. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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15 pages, 1552 KiB

Open AccessArticle

Low-Dose Empagliflozin Improves Systolic Heart Function after Myocardial Infarction in Rats: Regulation of MMP9, NHE1, and SERCA2a

by Jana Goerg, Manuela Sommerfeld, Bettina Greiner, Dilyara Lauer, Yasemin Seckin, Alexander Kulikov, Dmitry Ivkin, Ulrich Kintscher, Sergey Okovityi and Elena Kaschina

Int. J. Mol. Sci. 2021, 22(11), 5437; https://doi.org/10.3390/ijms22115437 - 21 May 2021

Cited by 23 | Viewed by 3282

Abstract

The effects of the selective sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in low dose on cardiac function were investigated in normoglycemic rats. Cardiac parameters were measured by intracardiac catheterization 30 min after intravenous application of empagliflozin to healthy animals. Empagliflozin increased the ventricular [...] Read more.

The effects of the selective sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in low dose on cardiac function were investigated in normoglycemic rats. Cardiac parameters were measured by intracardiac catheterization 30 min after intravenous application of empagliflozin to healthy animals. Empagliflozin increased the ventricular systolic pressure, mean pressure, and the max dP/dt (p < 0.05). Similarly, treatment with empagliflozin (1 mg/kg, p.o.) for one week increased the cardiac output, stroke volume, and fractional shortening (p < 0.05). Myocardial infarction (MI) was induced by ligation of the left coronary artery. On day 7 post MI, empagliflozin (1 mg/kg, p.o.) improved the systolic heart function as shown by the global longitudinal strain (−21.0 ± 1.1% vs. −16.6 ± 0.7% in vehicle; p < 0.05). In peri-infarct tissues, empagliflozin decreased the protein expression of matrix metalloproteinase 9 (MMP9) and favorably regulated the cardiac transporters sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA2a) and sodium hydrogen exchanger 1 (NHE1). In H9c2 cardiac cells, empagliflozin decreased the MMP2,9 activity and prevented apoptosis. Empagliflozin did not alter the arterial stiffness, blood pressure, markers of fibrosis, and necroptosis. Altogether, short-term treatment with low-dose empagliflozin increased the cardiac contractility in normoglycemic rats and improved the systolic heart function in the early phase after MI. These effects are attributed to a down-regulation of MMP9 and NHE1, and an up-regulation of SERCA2a. This study is of clinical importance because it suggests that a low-dose treatment option with empagliflozin may improve cardiovascular outcomes post-MI. Down-regulation of MMPs could be relevant to many remodeling processes including cancer disease. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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Review

Jump to: Editorial, Research

15 pages, 12566 KiB

Open AccessReview

The Role of the VEGF Family in Atherosclerosis Development and Its Potential as Treatment Targets

by Siarhei A. Dabravolski, Victoria A. Khotina, Andrey V. Omelchenko, Vladislav A. Kalmykov and Alexander N. Orekhov

Int. J. Mol. Sci. 2022, 23(2), 931; https://doi.org/10.3390/ijms23020931 - 15 Jan 2022

Cited by 38 | Viewed by 3390

Abstract

The vascular endothelial growth factor (VEGF) family, the crucial regulator of angiogenesis, lymphangiogenesis, lipid metabolism and inflammation, is involved in the development of atherosclerosis and further CVDs (cardiovascular diseases). This review discusses the general regulation and functions of VEGFs, their role in lipid [...] Read more.

The vascular endothelial growth factor (VEGF) family, the crucial regulator of angiogenesis, lymphangiogenesis, lipid metabolism and inflammation, is involved in the development of atherosclerosis and further CVDs (cardiovascular diseases). This review discusses the general regulation and functions of VEGFs, their role in lipid metabolism and atherosclerosis development and progression. These functions present the great potential of applying the VEGF family as a target in the treatment of atherosclerosis and related CVDs. In addition, we discuss several modern anti-atherosclerosis VEGFs-targeted experimental procedures, drugs and natural compounds, which could significantly improve the efficiency of atherosclerosis and related CVDs’ treatment. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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32 pages, 2419 KiB

Open AccessReview

Emerging Anti-Atherosclerotic Therapies

by Anna Gluba-Brzózka, Beata Franczyk, Magdalena Rysz-Górzyńska, Janusz Ławiński and Jacek Rysz

Int. J. Mol. Sci. 2021, 22(22), 12109; https://doi.org/10.3390/ijms222212109 - 09 Nov 2021

Cited by 10 | Viewed by 3727

Abstract

Cardiovascular disease (CAD) is the main cause of morbidity and deaths in the western world. The development of atherosclerosis underlying CAD development begins early in human life. There are numerous genetic and environmental risk factors accelerating its progression which then leads to the [...] Read more.

Cardiovascular disease (CAD) is the main cause of morbidity and deaths in the western world. The development of atherosclerosis underlying CAD development begins early in human life. There are numerous genetic and environmental risk factors accelerating its progression which then leads to the occurrence of acute events. Despite considerable progress in determining risk factors, there is still a lot of work ahead since identified determinants are responsible only for a part of overall CAD risk. Current therapies are insufficient to successfully reduce the risk of atherosclerosis development. Therefore, there is a need for effective preventive measures of clinical manifestations of atherosclerosis since the currently available drugs cannot prevent the occurrence of even 70% of clinical events. The shift of the target from lipid metabolism has opened the door to many new therapeutic targets. Currently, the majority of known targets for anti-atherosclerotic drugs focus also on inflammation (a common mediator of many risk factors), mechanisms of innate and adaptive immunity in atherosclerosis, molecule scavengers, etc. The therapeutic potential of cyclodextrins, protein kinase inhibitors, colchicine, inhibitors of p38 mitogen-activated protein kinase (MAPK), lipid dicarbonyl scavengers, a monoclonal antibody targeting interleukin-1β, and P-selectin inhibitors is still not fully confirmed and requires confirmation in large clinical trials. The preliminary results look promising. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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29 pages, 1627 KiB

Open AccessReview

Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

by Jorge Gutiérrez-Cuevas, Arturo Santos and Juan Armendariz-Borunda

Int. J. Mol. Sci. 2021, 22(21), 11629; https://doi.org/10.3390/ijms222111629 - 27 Oct 2021

Cited by 75 | Viewed by 8214

Abstract

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the [...] Read more.

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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29 pages, 1034 KiB

Open AccessReview

by Darja Smigoc Schweiger, Tadej Battelino and Urh Groselj

Int. J. Mol. Sci. 2021, 22(19), 10192; https://doi.org/10.3390/ijms221910192 - 22 Sep 2021

Cited by 10 | Viewed by 3034

Abstract

Cardiovascular disease (CVD) is the primary cause of higher and earlier morbidity and mortality in people with type 1 diabetes (T1D) compared to people without diabetes. In addition, women with T1D are at an even higher relative risk for CVD than men. However, [...] Read more.

Cardiovascular disease (CVD) is the primary cause of higher and earlier morbidity and mortality in people with type 1 diabetes (T1D) compared to people without diabetes. In addition, women with T1D are at an even higher relative risk for CVD than men. However, the underlying pathophysiology is not well understood. Atherosclerotic changes are known to progress early in life among people with T1D, yet it is less clear when excess CVD risk begins in females with T1D. This review explores the prevalence of classical CVD risk factors (such as glycemic control, hypertension, dyslipidemia, obesity, albuminuria, smoking, diet, physical inactivity), as well as of novel biomarkers (such as chronic inflammation), in children and adolescents with T1D with particular regard to sex-related differences in risk profile. We also summarize gaps where further research and clearer clinical guidance are needed to better address this issue. Considering that girls with T1D might have a more adverse CVD risk profile than boys, the early identification of and sex-specific intervention in T1D would have the potential to reduce later CVD morbidity and excess mortality in females with T1D. To conclude, based on an extensive review of the existing literature, we found a clear difference between boys and girls with T1D in the presence of individual CVD risk factors as well as in overall CVD risk profiles; the girls were on the whole more impacted. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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20 pages, 2605 KiB

Open AccessReview

The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis

by Margaret Vourakis, Gaétan Mayer and Guy Rousseau

Int. J. Mol. Sci. 2021, 22(15), 8074; https://doi.org/10.3390/ijms22158074 - 28 Jul 2021

Cited by 68 | Viewed by 8267

Abstract

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion [...] Read more.

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion by being implicated in several metabolic and inflammatory processes linked to several diseases including CVD. Studies have reported associations between bacterial metabolites and hypercholesterolemia. However, such associations remain poorly investigated and characterized. In this review, the mechanisms of microbial derived metabolites such as primary and secondary bile acids (BAs), trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) will be explored in the context of cholesterol metabolism. These metabolites play critical roles in maintaining cardiovascular health and if dysregulated can potentially contribute to CVD. They can be modulated via nutritional and pharmacological interventions such as statins, prebiotics, and probiotics. However, the mechanisms behind these interactions also remain unclear, and mechanistic insights into their impact will be provided. Therefore, the objectives of this paper are to present current knowledge on potential mechanisms whereby microbial metabolites regulate cholesterol homeostasis and to discuss the feasibility of modulating intestinal microbes and metabolites as a novel therapeutic for hypercholesterolemia. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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20 pages, 1468 KiB

Open AccessReview

Epigenetic Regulation of Autophagy in Cardiovascular Pathobiology

by Shuhan Bu and Krishna K. Singh

Int. J. Mol. Sci. 2021, 22(12), 6544; https://doi.org/10.3390/ijms22126544 - 18 Jun 2021

Cited by 9 | Viewed by 2608

Abstract

Cardiovascular diseases (CVDs) are the number one cause of debilitation and mortality worldwide, with a need for cost-effective therapeutics. Autophagy is a highly conserved catabolic recycling pathway triggered by various intra- or extracellular stimuli to play an essential role in development and pathologies, [...] Read more.

Cardiovascular diseases (CVDs) are the number one cause of debilitation and mortality worldwide, with a need for cost-effective therapeutics. Autophagy is a highly conserved catabolic recycling pathway triggered by various intra- or extracellular stimuli to play an essential role in development and pathologies, including CVDs. Accordingly, there is great interest in identifying mechanisms that govern autophagic regulation. Autophagic regulation is very complex and multifactorial that includes epigenetic pathways, such as histone modifications to regulate autophagy-related gene expression, decapping-associated mRNA degradation, microRNAs, and long non-coding RNAs; pathways are also known to play roles in CVDs. Molecular understanding of epigenetic-based pathways involved in autophagy and CVDs not only will enhance the understanding of CVDs, but may also provide novel therapeutic targets and biomarkers for CVDs. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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21 pages, 10555 KiB

Open AccessReview

Decoy Technology as a Promising Therapeutic Tool for Atherosclerosis

by Maryam Mahjoubin-Tehran, Yong Teng, Amin Jalili, Seyed Hamid Aghaee-Bakhtiari, Alexander M. Markin and Amirhossein Sahebkar

Int. J. Mol. Sci. 2021, 22(9), 4420; https://doi.org/10.3390/ijms22094420 - 23 Apr 2021

Cited by 5 | Viewed by 3323

Abstract

Cardiovascular diseases (CVDs) have been classified into several types of disease, of which atherosclerosis is the most prevalent. Atherosclerosis is characterized as an inflammatory chronic disease which is caused by the formation of lesions in the arterial wall. Subsequently, lesion progression and disruption [...] Read more.

Cardiovascular diseases (CVDs) have been classified into several types of disease, of which atherosclerosis is the most prevalent. Atherosclerosis is characterized as an inflammatory chronic disease which is caused by the formation of lesions in the arterial wall. Subsequently, lesion progression and disruption ultimately lead to heart disease and stroke. The development of atherosclerosis is the underlying cause of approximately 50% of all deaths in westernized societies. Countless studies have aimed to improve therapeutic approaches for atherosclerosis treatment; however, it remains high on the global list of challenges toward healthy and long lives. Some patients with familial hypercholesterolemia could not get intended LDL-C goals even with high doses of traditional therapies such as statins, with many of them being unable to tolerate statins because of the harsh side effects. Furthermore, even in patients achieving target LDL-C levels, the residual risk of traditional therapies is still significant thus highlighting the necessity of ongoing research for more effective therapeutic approaches with minimal side effects. Decoy-based drug candidates represent an opportunity to inhibit regulatory pathways that promote atherosclerosis. In this review, the potential roles of decoys in the treatment of atherosclerosis were described based on the in vitro and in vivo findings. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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Open AccessReview

Viral Infection and Cardiovascular Disease: Implications for the Molecular Basis of COVID-19 Pathogenesis

by Sarah Seeherman and Yuichiro J. Suzuki

Int. J. Mol. Sci. 2021, 22(4), 1659; https://doi.org/10.3390/ijms22041659 - 07 Feb 2021

Cited by 16 | Viewed by 4929

Abstract

The current pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While this respiratory virus only causes mild symptoms in younger healthy individuals, elderly people and those with cardiovascular diseases such as systemic hypertension are susceptible [...] Read more.

The current pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While this respiratory virus only causes mild symptoms in younger healthy individuals, elderly people and those with cardiovascular diseases such as systemic hypertension are susceptible to developing severe conditions that can be fatal. SARS-CoV-2 infection is also associated with an increased incidence of cardiovascular diseases such as myocardial injury, acute coronary syndrome, and thromboembolism. Understanding the mechanisms of the effects of this virus on the cardiovascular system should thus help develop therapeutic strategies to reduce the mortality and morbidity associated with SARS-CoV-2 infection. Since this virus causes severe and fatal conditions in older individuals with cardiovascular comorbidities, effective therapies targeting specific populations will likely contribute to ending this pandemic. In this review article, the effects of various viruses—including other coronaviruses, influenza, dengue, and human immunodeficiency virus—on the cardiovascular system are described to help provide molecular mechanisms of pathologies associated with SARS-CoV-2 infection and COVID-19. The goal is to provide mechanistic information from the biology of other viral infections in relation to cardiovascular pathologies for the purpose of developing improved vaccines and therapeutic agents effective in preventing and/or treating the acute and long-term consequences of SARS-CoV-2 and COVID-19. Full article

(This article belongs to the Special Issue Cardiovascular Diseases–a Focus on Atherosclerosis, Its Prophylaxis, Complications and Recent Advancements in Therapies)

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