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10 pages, 844 KiB

Open AccessArticle

Perhexiline Therapy in Patients with Type 2 Diabetes: Incremental Insulin Resistance despite Potentiation of Nitric Oxide Signaling

by Cher-Rin Chong, Saifei Liu, Hasan Imam, Tamila Heresztyn, Benedetta C. Sallustio, Yuliy Y. Chirkov and John D. Horowitz

Biomedicines 2022, 10(10), 2381; https://doi.org/10.3390/biomedicines10102381 - 23 Sep 2022

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Abstract

Perhexiline (Px) inhibits carnitine palmitoyltransferase 1 (CPT1), which controls uptake of long chain fatty acids into mitochondria. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory [...] Read more.

Perhexiline (Px) inhibits carnitine palmitoyltransferase 1 (CPT1), which controls uptake of long chain fatty acids into mitochondria. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may theoretically parallel insulin sensitization. We therefore sought to examine these relationships in patients with stable Type 2 diabetes (T2D) and cardiovascular disease (n = 30). Px was initiated, and dosage was titrated, to reach the therapeutic range and thus prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity and, utilizing aggregometry in whole blood, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP). Other parameters that affect may affect NO signalling were also evaluated. Px substantially potentiated inhibition of platelet aggregation by SNP (from 16.7 ± 3.0 to 27.3 ± 3.7%; p = 0.005). Px did not change fasting blood glucose concentrations but reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p = 0.028), and increased fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L; p = 0.014). Increases in SNP responses tended (r = −0.30; p = 0.11) to be reciprocally related to increases in HOMA-IR, and increases in HOMA-IR were greater (p = 0.002) in patients without NO-sensitizing effects. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px. Thus, in patients with stable T2D and cardiovascular disease, Px increases anti-aggregatory responsiveness to NO, but is not an insulin sensitizer, and does not induce hypoglycaemia. Absence of NO-sensitizing effect occurs in approximately 30% of Px-treated patients with T2D, and is associated with induction of insulin resistance in these patients. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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9 pages, 744 KiB

Open AccessCommunication

Granulocyte Colony-Stimulating Factor Ameliorates Endothelial Activation and Thrombotic Diathesis Biomarkers in a Murine Model of Hind Limb Ischemia

by Angeliki Valatsou, Panagiotis Theofilis, Spyridon Simantiris, Georgia Vogiatzi, Alexandros Briasoulis, Marios Sagris, Evangelos Oikonomou, Alexios S. Antonopoulos, Alkistis Pantopoulou, Narjes Nasiri-Ansari, Elizabeth Fragopoulou, Despoina Perrea, Konstantinos Tsioufis and Dimitris Tousoulis

Biomedicines 2022, 10(9), 2303; https://doi.org/10.3390/biomedicines10092303 - 16 Sep 2022

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Abstract

Novel therapies in peripheral arterial disease, such as granulocyte colony-stimulating factor (GCSF) administration, might result in anti-atherosclerotic effects. In this study, we used 10-week-old male ApoE^−/− mice, which were fed an atherosclerosis-inducing diet for four weeks. At the end of the four [...] Read more.

Novel therapies in peripheral arterial disease, such as granulocyte colony-stimulating factor (GCSF) administration, might result in anti-atherosclerotic effects. In this study, we used 10-week-old male ApoE^−/− mice, which were fed an atherosclerosis-inducing diet for four weeks. At the end of the four weeks, hind limb ischemia was induced through left femoral artery ligation, the atherosclerosis-inducing diet was discontinued, and a normal diet was initiated. Mice were then randomized into a control group (intramuscular 0.4 mL normal saline 0.9% for 7 days) and a group in which GCSF was administrated intramuscularly in the left hind limb for 7 days (100 mg/kg). In the GCSF group, but not in the control group, we observed significant reductions in the soluble adhesion molecules (vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1)), sE-Selectin, and plasminogen activator inhibitor (PAI)-1 when they were measured through ELISA on the 1st and the 28th days after hind limb ischemia induction. Therefore, GCSF administration in an atherosclerotic mouse model of hind limb ischemia led to decreases in the biomarkers associated with endothelial activation and thrombosis. These findings warrant further validation in future preclinical studies. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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15 pages, 750 KiB

Open AccessArticle

Relationship between the Soluble F11 Receptor and Annexin A5 in African Americans Patients with Type-2 Diabetes Mellitus

by Ajibola Adedayo, Ayobami Eluwole, Fasika Tedla, Arye Kremer, Muhammad Khan, Nicole Mastrogiovanni, Carl Rosenberg, Paul Dreizen, John La Rosa, Louis Salciccioli, Mohamed Boutjdir, Mary Ann Banerji, Clinton Brown, Jason Lazar, Moro Salifu and Ahmed Bakillah

Biomedicines 2022, 10(8), 1818; https://doi.org/10.3390/biomedicines10081818 - 28 Jul 2022

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Abstract

Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity, and inflammation. The soluble human F11 receptor (sF11R) and annexin A5 (ANXA5) play crucial roles in inflammatory thrombosis and atherosclerosis. We examined the relationship between circulating sF11R and ANXA5 and their [...] Read more.

Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity, and inflammation. The soluble human F11 receptor (sF11R) and annexin A5 (ANXA5) play crucial roles in inflammatory thrombosis and atherosclerosis. We examined the relationship between circulating sF11R and ANXA5 and their impact on endothelial function. The study included 125 patients with T2DM. Plasma levels of sF11R and ANXA5 were quantified by ELISA. Microvascular function was assessed using the vascular reactivity index (VRI). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV). Carotid intima-media thickness (CIMT) was assessed by B-mode ultrasound imaging. The mean age of patients in the study was 59.7 ± 7.8 years, 78% had hypertension, 76% had dyslipidemia, and 12% had CKD. sF11R correlated positively with ANXA5 levels (β = 0.250, p = 0.005), and correlated inversely with VRI and total nitic oxide (NO), (β = −0.201, p = 0.024; β = −0.357, p = 0.0001, respectively). Multivariate regression analysis revealed that sF11R was independently associated with ANXA5 in the total population and in patients with HbA1c > 6.5% (β = 0.366, p = 0.007; β = 0.425, p = 0.0001, respectively). sF11R and ANXA5 were not associated with vascular outcome, suggesting that they may not be reliable markers of vascular dysfunction in diabetes. The clinical significance of sF11R/ANXA5 association in diabetes warrants further investigation in a larger population. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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15 pages, 1066 KiB

Open AccessArticle

The Effect of SGLT2 Inhibitor Dapagliflozin on Serum Levels of Apelin in T2DM Patients with Heart Failure

by Alexander A. Berezin, Ivan M. Fushtey and Alexander E. Berezin

Biomedicines 2022, 10(7), 1751; https://doi.org/10.3390/biomedicines10071751 - 20 Jul 2022

Cited by 6 | Viewed by 2112

Abstract

Apelin is a multifunctional peptide that plays a pivotal role in cardiac remodeling and HF manifestation because of counteracting angiotensin-II. We hypothesized that positive influence of sodium-glucose co-transporter-2 (SGLT2) inhibitor on cardiac function in T2DM patients with HF might be mediated by apelin [...] Read more.

Apelin is a multifunctional peptide that plays a pivotal role in cardiac remodeling and HF manifestation because of counteracting angiotensin-II. We hypothesized that positive influence of sodium-glucose co-transporter-2 (SGLT2) inhibitor on cardiac function in T2DM patients with HF might be mediated by apelin and that its levels seem to be a target of management. A total of 153 type 2 diabetes mellitus (T2DM) patients with II/III HF NYHA class and average left ventricular (LV) ejection fraction (EF) of 46% have been enrolled and treated with dapagliflosin. The serum levels of apelin and N-terminal brain natriuretic pro-peptide (NT-proBNP) were measured at baseline and over a 6-month period of dapagliflosin administration. We noticed that administration of dapagliflozin was associated with a significant increase in apelin levels of up to 18.3% and a decrease in NT-proBNP of up to 41.0%. Multivariate logistic regression showed that relative changes of LVEF, LA volume index, and early diastolic blood filling to longitudinal strain ratio were strongly associated with the levels of apelin, whereas NT-proBNP exhibited a borderline significance in this matter. In conclusion, dapagiflosin exerted a positive impact on echocardiographic parameters in close association with an increase in serum apelin levels, which could be a surrogate target for HF management. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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16 pages, 2219 KiB

Open AccessArticle

A Factor XIa Inhibitor Engineered from Banded Krait Venom Toxin: Efficacy and Safety in Rodent Models of Arterial and Venous Thrombosis

by Wei Seng Chng, Aaron Wei Liang Li, Jasmine Jia Min Lim, Esther Jia En Leong, Fathiah S. Amran, R. Manjunatha Kini, Mark Yan Yee Chan and Cho Yeow Koh

Biomedicines 2022, 10(7), 1679; https://doi.org/10.3390/biomedicines10071679 - 12 Jul 2022

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Abstract

Activated factor XI (FXIa) is an important antithrombotic drug target. Clinical and pre-clinical data have demonstrated that its inhibition attenuates thrombosis with minimal risk of excessive bleeding. We isolated Fasxiator from the venom of banded krait Bungarus fasciatus and subsequently engineered Fasxiator_N17R,L19E [...] Read more.

Activated factor XI (FXIa) is an important antithrombotic drug target. Clinical and pre-clinical data have demonstrated that its inhibition attenuates thrombosis with minimal risk of excessive bleeding. We isolated Fasxiator from the venom of banded krait Bungarus fasciatus and subsequently engineered Fasxiator_N17R,L19E, with improved affinity (K_i = 0.9 nM) and selectivity towards FXIa. Here, we assess the in vivo efficacy and bleeding risk of rFasxiator_{N17R, L19E} in pre-clinical animal models. Rats injected intravenously (i.v.) with bolus rFasxiator_{N17R, L19E} showed the specific in vivo attenuation of the intrinsic coagulation pathway, lasting for at least 60 min. We performed the in vivo dose-ranging experiments for rFasxiator_{N17R, L19E} as follows: FeCl₃-induced carotid artery occlusion in rats (arterial thrombosis); inferior vena cava ligation in mice (venous thrombosis); tail bleeding time in both rats and mice (bleeding risk). Head-to-head comparisons were made using therapeutic dosages of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) for arterial and venous thrombosis, respectively. In the arterial thrombosis model, 2 mg/kg i.v. rFasxiator_N17R,L19E achieved a similar antithrombotic efficacy to that of UFH, with >3-fold lower bleeding time. In the venous thrombosis model, the 10 mg/kg subcutaneous (s.c.) injection of rFasxiator_N17R,L19E achieved similar efficacy and bleeding levels to those of LMWH enoxaparin. Overall, rFasxiator_N17R,L19E represents a promising molecule for the development of FXIa-targeting anticoagulants. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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11 pages, 1214 KiB

Open AccessArticle

Comparing the Effects of Canagliflozin vs. Glimepiride by Body Mass Index in Patients with Type 2 Diabetes and Chronic Heart Failure: A Subanalysis of the CANDLE Trial

by Akira Sezai, Atsushi Tanaka, Takumi Imai, Keisuke Kida, Hisakuni Sekino, Toyoaki Murohara, Masataka Sata, Norio Suzuki and Koichi Node

Biomedicines 2022, 10(7), 1656; https://doi.org/10.3390/biomedicines10071656 - 09 Jul 2022

Cited by 1 | Viewed by 1650

Abstract

Background: We present results of a 24-week comparative study of the effects of the sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin vs. the sulfonylurea glimepiride, by baseline body mass index (BMI), in patients with type 2 diabetes and chronic heart failure. Methods: We conducted [...] Read more.

Background: We present results of a 24-week comparative study of the effects of the sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin vs. the sulfonylurea glimepiride, by baseline body mass index (BMI), in patients with type 2 diabetes and chronic heart failure. Methods: We conducted a post hoc analysis of the CANDLE trial. This subanalysis evaluated NT-proBNP, BMI, and other laboratory parameters, according to the subgroups stratified by BMI ≥ 25 kg/m² vs. BMI < 25 kg/m². Results: A group ratio of proportional changes in the geometric means of NT-proBNP was 0.99 (p = 0.940) for the subgroup with BMI ≥ 25 kg/m² and 0.85 (p = 0.075) for the subgroup with BMI < 25 kg/m², respectively. When baseline BMI was modeled as a continuous variable, results for patients with BMI < 30 kg/m² showed a slightly smaller increase in NT-proBNP in the canagliflozin group vs. the glimepiride group (p = 0.295); that difference was not seen among patients with BMI ≥30 kg/m² (p = 0.948). Irrespective of obesity, the canagliflozin group was associated with significant reduction in BMI compared to the glimepiride group. Conclusion: There was no significant difference in the effects of canagliflozin, relative to glimepiride, on NT-proBNP concentrations irrespective of baseline obesity. UMIN clinical trial registration number: UMIN000017669. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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15 pages, 3678 KiB

Open AccessArticle

Klotho Modulates Pro-Fibrotic Activities in Human Atrial Fibroblasts through Inhibition of Phospholipase C Signaling and Suppression of Store-Operated Calcium Entry

by Yuan Hung, Cheng-Chih Chung, Yao-Chang Chen, Yu-Hsun Kao, Wei-Shiang Lin, Shih-Ann Chen and Yi-Jen Chen

Biomedicines 2022, 10(7), 1574; https://doi.org/10.3390/biomedicines10071574 - 01 Jul 2022

Cited by 2 | Viewed by 1530

Abstract

Background: Atrial fibroblasts activation causes atrial fibrosis, which is one major pathophysiological contributor to atrial fibrillation (AF) genesis. Klotho is a pleiotropic protein with remarkable cardiovascular effects, including anti-inflammatory, anti-oxidative, and anti-apoptotic effects. This study investigated whether Klotho can modulate the activity of [...] Read more.

Background: Atrial fibroblasts activation causes atrial fibrosis, which is one major pathophysiological contributor to atrial fibrillation (AF) genesis. Klotho is a pleiotropic protein with remarkable cardiovascular effects, including anti-inflammatory, anti-oxidative, and anti-apoptotic effects. This study investigated whether Klotho can modulate the activity of human atrial fibroblasts and provides an anti-fibrotic effect. Methods: Cell migration assay and proliferation assay were used to investigate fibrogenesis activities in single human atrial fibroblasts with or without treatment of Klotho (10 and 100 pM, 48 h). Calcium fluorescence imaging, the whole-cell patch-clamp, and Western blotting were performed in human atrial fibroblasts treated with and without Klotho (100 pM, 48 h) to evaluate the store-operated calcium entry (SOCE), transient receptor potential (TRP) currents, and downstream signaling. Results: High dose of Klotho (100 pM, 48 h) significantly reduced the migration of human atrial fibroblasts without alternating their proliferation; in addition, treatment of Klotho (100 pM, 48 h) also decreased SOCE and TRP currents. In the presence of BI-749327 (a selective canonical TRP 6 channel inhibitor, 1 μM, 48 h), Klotho (100 pM, 48 h) could not inhibit fibroblast migration nor suppress the TRP currents. Klotho-treated fibroblasts (100 pM, 48 h) had lower phosphorylated phospholipase C (PLC) (p-PLCβ3 Ser537) expression than the control. The PLC inhibitor, U73122 (1 μM, 48 h), reduced the migration, decreased SOCE and TRP currents, and lowered p-PLCβ3 in atrial fibroblasts, similar to Klotho. In the presence of the U73122 (1 μM, 48 h), Klotho (100 pM, 48 h) could not further modulate the migration and collagen synthesis nor suppress the TRP currents in human atrial fibroblasts. Conclusions: Klotho inhibited pro-fibrotic activities and SOCE by inhibiting the PLC signaling and suppressing the TRP currents, which may provide a novel insight into atrial fibrosis and arrhythmogenesis. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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14 pages, 1275 KiB

Open AccessArticle

Gender Differences in Non-Persistence with Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers among Older Hypertensive Patients with Peripheral Arterial Disease

by Martin Wawruch, Jan Murin, Tomas Tesar, Martina Paduchova, Miriam Petrova, Denisa Celovska, Beata Havelkova, Michal Trnka, Lucia Masarykova, Sofa D. Alfian and Emma Aarnio

Biomedicines 2022, 10(7), 1479; https://doi.org/10.3390/biomedicines10071479 - 22 Jun 2022

Cited by 3 | Viewed by 1355

Abstract

The beneficial effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in hypertensive patients with peripheral arterial disease (PAD) depends on long-term persistence. The aims of our study were to analyse gender differences in non-persistence with ACEIs/ARBs, and to identify the [...] Read more.

The beneficial effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in hypertensive patients with peripheral arterial disease (PAD) depends on long-term persistence. The aims of our study were to analyse gender differences in non-persistence with ACEIs/ARBs, and to identify the characteristics associated with the likelihood of non-persistence. Our study cohort included 7080 hypertensive patients (4005 women and 3075 men) aged ≥65 years, treated with ACEIs/ARBs, in whom PAD was diagnosed between 1 January and 31 December 2012. Non-persistence was identified according to a treatment gap of 6 months without ACEI/ARB prescriptions. The characteristics associated with non-persistence were identified using the Cox regression model. At the end of the 5-year follow-up, 23.2% of the whole study cohort, 22.3% of men, and 23.9% of women were non-persistent with ACEIs/ARBs, with no significant gender differences in persistence. While a number of characteristics were associated with non-persistence, only three characteristics had consistent, statistically significant associations in both genders: being a new ACEI/ARB user increased the likelihood of non-persistence, and general practitioner as index prescriber and increasing the overall number of medications decreased the likelihood of non-persistence. Information on the differences in characteristics that are associated with non-persistence between genders may help to better identify patients for whom special attention should be paid to improve their persistence. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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12 pages, 2584 KiB

Open AccessArticle

Epigallocatechin-3-Gallate (EGCG) Mitigates Endothelial and Circulating Cells Alterations Following PLLA Electrospun Mat Placement

by Carmen Ciavarella, Ilenia Motta, Santino Blando, Sabrina Valente, Fulvia Farabegoli, Maria Letizia Focarete, Mauro Gargiulo and Gianandrea Pasquinelli

Biomedicines 2022, 10(6), 1276; https://doi.org/10.3390/biomedicines10061276 - 30 May 2022

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Abstract

Background. Synthetic vascular graft calcification is a serious complication of graft placement. Here, we analysed migration and osteogenic genes of human umbilical vein endothelial cells (HUVEC) cultured with a poly-L-lactic acid (PLLA) electrospun mat. The role of epigallo-catechin-3-gallate (EGCG) in pathogenic processes involving [...] Read more.

Background. Synthetic vascular graft calcification is a serious complication of graft placement. Here, we analysed migration and osteogenic genes of human umbilical vein endothelial cells (HUVEC) cultured with a poly-L-lactic acid (PLLA) electrospun mat. The role of epigallo-catechin-3-gallate (EGCG) in pathogenic processes involving HUVEC and peripheral blood mononuclear cells (PBMCs) was also tested. Methods. HUVEC were cultured in indirect contact with PLLA for 48 h, with or without EGCG, and processed for mRNA expression. HUVEC proliferation, migration and osteogenic differentiation were evaluated after EGCG treatment. EGCG was also administrated to human PBMCs, to analyse proliferation and migration toward HUVEC cultured with PLLA. Results. HUVEC cultured with PLLA exhibited increased expression of SLUG, VIMENTIN, MMP-9 (migration, vascular remodelling) and RUNX-2 (osteogenic transcription factor). EGCG at 25 μM significantly reduced HUVEC migration, osteogenic differentiation, without affecting cell viability, and mitigated PLLA influence on SLUG, MMP-9, VIMENTIN and RUNX-2 expression. EGCG affected PBMC proliferation and migration toward PLLA in a transwell co-culture system with HUVEC. Conclusion. Our study suggests the pro-calcific effect of PLLA, proposing EGCG as an anti-inflammatory modulatory approach. Research efforts need to deepen PLLA-vascular wall interactions for preventing vascular graft failure. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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21 pages, 2340 KiB

Open AccessArticle

Drug-Targeted Genomes: Mutability of Ion Channels and GPCRs

by Regan Raines, Ian McKnight, Hunter White, Kaitlyn Legg, Chan Lee, Wei Li, Peter H. U. Lee and Joon W. Shim

Biomedicines 2022, 10(3), 594; https://doi.org/10.3390/biomedicines10030594 - 03 Mar 2022

Cited by 6 | Viewed by 2845

Abstract

Mutations of ion channels and G-protein-coupled receptors (GPCRs) are not uncommon and can lead to cardiovascular diseases. Given previously reported multiple factors associated with high mutation rates, we sorted the relative mutability of multiple human genes by (i) proximity to telomeres and/or (ii) [...] Read more.

Mutations of ion channels and G-protein-coupled receptors (GPCRs) are not uncommon and can lead to cardiovascular diseases. Given previously reported multiple factors associated with high mutation rates, we sorted the relative mutability of multiple human genes by (i) proximity to telomeres and/or (ii) high adenine and thymine (A+T) content. We extracted genomic information using the genome data viewer and examined the mutability of 118 ion channel and 143 GPCR genes based on their association with factors (i) and (ii). We then assessed these two factors with 31 genes encoding ion channels or GPCRs that are targeted by the United States Food and Drug Administration (FDA)-approved drugs. Out of the 118 ion channel genes studied, 80 met either factor (i) or (ii), resulting in a 68% match. In contrast, a 78% match was found for the 143 GPCR genes. We also found that the GPCR genes (n = 20) targeted by FDA-approved drugs have a relatively lower mutability than those genes encoding ion channels (n = 11), where targeted genes encoding GPCRs were shorter in length. The result of this study suggests that the use of matching rate analysis on factor-druggable genome is feasible to systematically compare the relative mutability of GPCRs and ion channels. The analysis on chromosomes by two factors identified a unique characteristic of GPCRs, which have a significant relationship between their nucleotide sizes and proximity to telomeres, unlike most genetic loci susceptible to human diseases. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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10 pages, 1273 KiB

Open AccessArticle

Purinergic Receptor P2Y2 Stimulation Averts Aortic Valve Interstitial Cell Calcification and Myofibroblastic Activation

by Donato Moschetta, Enrico Di Maria, Vincenza Valerio, Ilaria Massaiu, Michele Bozzi, Paola Songia, Yuri D’alessandra, Veronika A. Myasoedova and Paolo Poggio

Biomedicines 2022, 10(2), 457; https://doi.org/10.3390/biomedicines10020457 - 16 Feb 2022

Cited by 1 | Viewed by 2043

Abstract

Rationale—Calcific aortic valve stenosis (CAVS) is a pathological condition of the aortic valve with a prevalence of 3% in the general population. It is characterized by massive rearrangement of the extracellular matrix, mostly due to the accumulation of fibro-calcific deposits driven by valve [...] Read more.

Rationale—Calcific aortic valve stenosis (CAVS) is a pathological condition of the aortic valve with a prevalence of 3% in the general population. It is characterized by massive rearrangement of the extracellular matrix, mostly due to the accumulation of fibro-calcific deposits driven by valve interstitial cells (VIC), and no pharmacological treatment is currently available. The aim of this study was to evaluate the effects of P2Y2 receptor (P2RY2) activation on fibro-calcific remodeling of CAVS. Methods—We employed human primary VICs isolated from CAVS leaflets treated with 2-thiouridine-5′-triphosphate (2ThioUTP, 10 µM), an agonist of P2RY2. The calcification was induced by inorganic phosphate (2 mM) and ascorbic acid (50 µg/mL) for 7 or 14 days, while the 2ThioUTP was administered starting from the seventh day. 2ThioUTP was chronically administered for 5 days to evaluate myofibroblastic activation. Results—P2RY2 activation, under continuous or interrupted pro-calcific stimuli, led to a significant inhibition of VIC calcification potential (p < 0.01). Moreover, 2ThioUTP treatment was able to significantly reduce pro-fibrotic gene expression (p < 0.05), as well as that of protein α-smooth muscle actin (p = 0.004). Conclusions—Our data suggest that P2RY2 activation should be further investigated as a pharmacological target for the prevention of CAVS progression, acting on both calcification and myofibroblastic activation. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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18 pages, 653 KiB

Open AccessReview

Haematological Drugs Affecting Lipid Metabolism and Vascular Health

by Antonio Parrella, Arcangelo Iannuzzi, Mario Annunziata, Giuseppe Covetti, Raimondo Cavallaro, Emilio Aliberti, Elena Tortori and Gabriella Iannuzzo

Biomedicines 2022, 10(8), 1935; https://doi.org/10.3390/biomedicines10081935 - 10 Aug 2022

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Abstract

Many drugs affect lipid metabolism and have side effects which promote atherosclerosis. The prevalence of cancer-therapy-related cardiovascular (CV) disease is increasing due to development of new drugs and improved survival of patients: cardio-oncology is a new field of interest and research. Moreover, drugs [...] Read more.

Many drugs affect lipid metabolism and have side effects which promote atherosclerosis. The prevalence of cancer-therapy-related cardiovascular (CV) disease is increasing due to development of new drugs and improved survival of patients: cardio-oncology is a new field of interest and research. Moreover, drugs used in transplanted patients frequently have metabolic implications. Increasingly, internists, lipidologists, and angiologists are being consulted by haematologists for side effects on metabolism (especially lipid metabolism) and arterial circulation caused by drugs used in haematology. The purpose of this article is to review the main drugs used in haematology with side effects on lipid metabolism and atherosclerosis, detailing their mechanisms of action and suggesting the most effective therapies. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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19 pages, 2050 KiB

Open AccessReview

Optimizing Therapies in Heart Failure: The Role of Potassium Binders

by Pietro Scicchitano, Massimo Iacoviello, Francesco Massari, Micaela De Palo, Pasquale Caldarola, Antonia Mannarini, Andrea Passantino, Marco Matteo Ciccone and Michele Magnesa

Biomedicines 2022, 10(7), 1721; https://doi.org/10.3390/biomedicines10071721 - 16 Jul 2022

Cited by 4 | Viewed by 3107

Abstract

Heart failure (HF) is a worrisome cardiac pandemic with a negative prognostic impact on the overall survival of individuals. International guidelines recommend up-titration of standardized therapies in order to reduce symptoms, hospitalization rates, and cardiac death. Hyperkalemia (HK) has been identified in 3–18% [...] Read more.

Heart failure (HF) is a worrisome cardiac pandemic with a negative prognostic impact on the overall survival of individuals. International guidelines recommend up-titration of standardized therapies in order to reduce symptoms, hospitalization rates, and cardiac death. Hyperkalemia (HK) has been identified in 3–18% of HF patients from randomized controlled trials and over 25% of HF patients in the “real world” setting. Pharmacological treatments and/or cardio-renal syndrome, as well as chronic kidney disease may be responsible for HK in HF patients. These conditions can prevent the upgrade of pharmacological treatments, thus, negatively impacting on the overall prognosis of patients. Potassium binders may be the best option in patients with HK in order to reduce serum concentrations of K⁺ and to promote correct upgrades of therapies. In addition to the well-established use of sodium polystyrene sulfonate (SPS), two novel drugs have been recently introduced: sodium zirconium cyclosilicate (SZC) and patiromer. SZC and patiromer are gaining a central role for the treatment of chronic HK. SZC has been shown to reduce K⁺ levels within 48 h, with guaranteed maintenance of normokalemia for up to12 months. Patiromer has resulted in a statistically significant decrease in serum potassium for up to 52 weeks. Therefore, long-term results seemed to positively promote the implementation of these compounds in clinical practice due to their low rate side effects. The aim of this narrative review is to delineate the impact of new potassium binders in the treatment of patients with HF by providing a critical reappraisal for daily application of novel therapies for hyperkalemia in the HF setting. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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