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New Advance in Cardiovascular Drugs: In Celebration of the 90th...
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New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 6536

Special Issue Editor

Dr. Alfredo Caturano

E-Mail Website
Guest Editor
Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy
Interests: cardiovascular (CV) risk; diabetes; heart failure (HF); metformin; diabetes complications
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We dedicate this Special Issue in celebration of the 90th birthday of Prof. Akira Endo, an internationally renowned Japanese biochemist whose research into the relationship between fungi and cholesterol biosynthesis led to the development of the first statin (ML-236B; compactin) 50 years ago, providing a relevant contribution to the advance of cardiovascular pharmacology.

Prof. Akira Endo (born 14 November 1933, in Higashiyuri, Northern Japan) developed an interest in fungi since young age, being an admirer of Alexander Fleming. He degreed from the Faculty of Agriculture at Tokohu University in 1957 and started working as a research fellow in the pharmaceutical company Sankyo, in Tokyo. His research focused on fungal enzymes for processing fruit juice, and, due to successful discoveries in the field, moved to New York after receiving his PhD from the Tokohu University in 1966. In New York, he spent 2 years as a research associate at the Albert Einstein College of Medicine and worked on cholesterol, before returning to Sankyo’s research laboratories in 1968. It was here that Prof. Endo speculated that some fungi might produce antibiotics to inhibit the enzyme responsible for the rate-limiting step in cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, possibly as a defence mechanism against other microbes. Prof. Endo started his exploratory research in April 1971, analysing about 6000 compounds, and discovered the first statin mevastatin (ML-236B; compactin) in 1973. The wind of change that would have brought such a discovery was not yet known. In fact, at that time, little was known about low-density lipoprotein (LDL) regulation mechanisms since Brown and Goldstein only began their studies that would have led to the discovery of LDL receptor in 1972. As statin research gained attention, other pharmaceutical companies joined in and, in 1978, Merck isolated a compactin-like substance from Aspergillus terreus, whilst, simultaneously, the same compound was discovered by Prof. Endo from Monascus ruber, and lovastatin was born. It took over 10 years preclinical and clinical trials before the approval and commercialization of lovastatin that occurred in 1987 in USA, also paving the way for further statin drugs development.

Prof. Endo became an associate professor in the late 1970s and in 1986 a full professor at Tokyo University of Agriculture and Technology, where he enlightened the minds of young researchers until his retirement. After his official retirement, he became the president of Biopharm Research Laboratories. Thanks to Prof. Endo’s perseverance and enthusiasm in deepening his research, statins are now used to prevent cardiovascular events globally, as well as improving the quality of life of patients.

In this commemorative Special Issue, the scope of which is to detail the advances in cardiovascular drugs in the last few decades, we welcome scientific contributions with the aim of gathering accurate and up-to-date scientific information on laboratory studies of new and upcoming treatment opportunities for cardiovascular diseases. It is my privilege to invite you and your co-workers to share their experience and expertise by submitting original research articles, systematic reviews, and review articles reporting new ideas and recent advances related to this topic.

Dr. Alfredo Caturano
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cardiovascular drugs
  • statins
  • metformin
  • SGLT2i
  • laboratory
  • drug targets
  • translational research
  • targeted therapy

Published Papers (6 papers)

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Research

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20 pages, 1820 KiB  
Article
Atorvastatin Treatment Significantly Increased the Concentration of Bone Marrow-Derived Mononuclear Cells and Transcutaneous Oxygen Pressure and Lowered the Pain Scale after Bone Marrow Cells Treatment in Patients with “No-Option” Critical Limb Ischaemia
by Jan Kyselovic, Adriana Adamičková, Andrea Gažová, Simona Valášková, Nikola Chomaničová, Zdenko Červenák and Juraj Madaric
Biomedicines 2024, 12(4), 922; https://doi.org/10.3390/biomedicines12040922 - 22 Apr 2024
Viewed by 349
Abstract
Background: The present study investigated the outcomes and possible predictive factors of autologous bone marrow cells (BMCs) therapy in patients with ”no-option“ critical limb ischaemia (CLI). It was focused on exploring the clinical background and prior statin and renin-angiotensin system (RAS)-acting agents pharmacotherapy [...] Read more.
Background: The present study investigated the outcomes and possible predictive factors of autologous bone marrow cells (BMCs) therapy in patients with ”no-option“ critical limb ischaemia (CLI). It was focused on exploring the clinical background and prior statin and renin-angiotensin system (RAS)-acting agents pharmacotherapy related to the therapeutic efficacy of BMCs treatment. Methods: In the present study, we reviewed thirty-three patients (mean age 64.9 ± 10 years; 31 males) with advanced CLI after failed or impossible revascularisation, who were treated with 40 mL of autologous BMCs by local intramuscular application. Patients with limb salvage and wound healing (N = 22) were considered as responders to BMCs therapy, and patients with limb salvage and complete ischemic wound healing (N = 13) were defined as super-responders. Logistic regression models were used to screen and identify the prognostic factors, and a receiver operating characteristics (ROC) curve, a linear regression, and a survival curve were drawn to determine the predictive accuracy, the correlation between the candidate predictors, and the risk of major amputation. Results: Based on the univariate regression analysis, baseline C-reactive protein (CRP) and transcutaneous oxygen pressure (TcPO2) values were identified as prognostic factors of the responders, while CRP value, ankle-brachial index (ABI), and bone marrow-derived mononuclear cells (BM-MNCs) concentration were identified as prognostic factors of the super-responders. An area under the ROC curve of 0.768 indicated good discrimination for CRP > 8.1 mg/L before transplantation as a predictive factor for negative clinical response. Linear regression analysis revealed a significant dependence between the levels of baseline CRP and the concentration of BM-MNCs in transplanted bone marrow. Patients taking atorvastatin before BMCs treatment (N = 22) had significantly improved TcPO2 and reduced pain scale after BMCs transplant, compared to the non-atorvastatin group. Statin treatment was associated with reduced risk for major amputation. However, the difference was not statistically significant. Statin use was also associated with a significantly higher concentration of BM-MNCs in the transplanted bone marrow compared to patients without statin treatment. Patients treated with RAS-acting agents (N = 20) had significantly reduced pain scale after BMCs transplant, compared to the non-RAS-acting agents group. Similar results, reduced pain scale and improved TcPO2, were achieved in patients treated with atorvastatin and RAS-acting agents (N = 17) before BMCs treatment. Results of the Spearman correlation showed a significant positive correlation between CLI regression, responders, and previous therapy before BMCs transplant with RAS-acting agents alone or with atorvastatin. Conclusions: CRP and TcPO2 were prognostic factors of the responders, while CRP value, ABI, and BM-MNCs concentration were identified as predictive factors of the super-responders. Atorvastatin treatment was associated with a significantly increased concentration of BM-MNCs in bone marrow concentrate and higher TcPO2 and lower pain scale after BMCs treatment in CLI patients. Similarly, reduced pain scales and improved TcPO2 were achieved in patients treated with atorvastatin and RAS-acting agents before BMCs treatment. Positive correlations between responders and previous treatment before BMCs transplant with RAS-acting agents alone or with atorvastatin were significant. Full article
(This article belongs to the Special Issue New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo)
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16 pages, 2874 KiB  
Article
Sacubitril/Valsartan Alleviates Cardiac Remodeling and Dysfunction in L-NAME-Induced Hypertension and Hypertensive Heart Disease
by Peter Stanko, Kristina Repova, Tomas Baka, Kristina Krajcirovicova, Silvia Aziriova, Andrej Barta, Stefan Zorad, Michaela Adamcova and Fedor Simko
Biomedicines 2024, 12(4), 733; https://doi.org/10.3390/biomedicines12040733 - 25 Mar 2024
Viewed by 599
Abstract
There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart disease are sparse. The aim of this study was to show whether an ARNI exerts a [...] Read more.
There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart disease are sparse. The aim of this study was to show whether an ARNI exerts a protective effect in a model of Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension with a hypertensive heart and to compare this potential benefit with an angiotensin-converting enzyme inhibitor, captopril. Five groups of adult male Wistar rats were studied (14 per group) for four weeks: untreated controls; ARNI (68 mg/kg/day); L-NAME (40 mg/kg/day); L-NAME treated with ARNI; and L-NAME treated with captopril (100 mg/kg/day). L-NAME administration induced hypertension, accompanied by increased left ventricular (LV) weight and fibrotic rebuilding of the LV in terms of increased concentration and content of hydroxyproline in insoluble collagen and in total collagen and with a histological finding of fibrosis. These alterations were associated with a compromised systolic and diastolic LV function. Treatment with either an ARNI or captopril reduced systolic blood pressure (SBP), alleviated LV hypertrophy and fibrosis, and prevented the development of both systolic and diastolic LV dysfunction. Moreover, the serum levels of prolactin and prolactin receptor were reduced significantly by ARNI and slightly by captopril. In conclusion, in L-NAME-induced hypertension, the dual inhibition of neprilysin and AT1 receptors by ARNI reduced SBP and prevented the development of LV hypertrophy, fibrosis, and systolic and diastolic dysfunction. These data suggest that ARNI could provide protection against LV structural remodeling and functional disorders in hypertensive heart disease. Full article
(This article belongs to the Special Issue New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo)
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15 pages, 3121 KiB  
Article
Repurposing of the Cardiovascular Drug Statin for the Treatment of Cancers: Efficacy of Statin–Dipyridamole Combination Treatment in Melanoma Cell Lines
by Nanami Irie, Kana Mizoguchi, Tomoko Warita, Mirai Nakano, Kasuga Sasaki, Jiro Tashiro, Tomohiro Osaki, Takuro Ishikawa, Zoltán N. Oltvai and Katsuhiko Warita
Biomedicines 2024, 12(3), 698; https://doi.org/10.3390/biomedicines12030698 - 21 Mar 2024
Viewed by 1016
Abstract
Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, [...] Read more.
Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility. Full article
(This article belongs to the Special Issue New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo)
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14 pages, 972 KiB  
Article
Cardioprotective Activity of Pharmacological Agents Affecting NO Production and Bioavailability in the Early Postnatal Period after Intrauterine Hypoxia in Rats
by Olena Popazova, Igor Belenichev, Nina Bukhtiyarova, Victor Ryzhenko, Valentyn Oksenych and Aleksandr Kamyshnyi
Biomedicines 2023, 11(10), 2854; https://doi.org/10.3390/biomedicines11102854 - 21 Oct 2023
Cited by 3 | Viewed by 1256
Abstract
Intrauterine hypoxia in newborns leads to a multifaceted array of alterations that exert a detrimental impact on the cardiovascular system. The aim of this research was to assess the cardioprotective effects of modulators of the nitric oxide (NO) system, including L-arginine, Thiotriazoline, Angiolin, [...] Read more.
Intrauterine hypoxia in newborns leads to a multifaceted array of alterations that exert a detrimental impact on the cardiovascular system. The aim of this research was to assess the cardioprotective effects of modulators of the nitric oxide (NO) system, including L-arginine, Thiotriazoline, Angiolin, and Mildronate, during the early postnatal period following intrauterine hypoxia. Methods: The study involved 50 female white rats. Pregnant female rats were given a daily intraperitoneal dose of 50 mg/kg of sodium nitrite starting on the 16th day of pregnancy. A control group of pregnant rats received saline instead. The resulting offspring were divided into the following groups: Group 1—intact rats; Group 2—rat pups subjected to prenatal hypoxia (PH) and daily treated with physiological saline; and Groups 3 to 6—rat pups exposed to prenatal hypoxia and treated daily from the 1st to the 30th day after birth. Nitrotyrosine levels, eNOS, iNOS, and NO metabolites were evaluated using ELISA; to measure the expression levels of iNOS mRNA and eNOS mRNA, a PCR test was utilized. Results: Angiolin enhances the expression of eNOS mRNA and boosts eNOS activity in the myocardium of rats with ischemic conditions. Arginine and particularly Thiotriazoline exhibited a consistent impact in restoring normal parameters of the cardiac nitroxidergic system following PH. Mildronate notably raised iNOS mRNA levels and notably reduced nitrotyrosine levels, providing further support for its antioxidative characteristics. Full article
(This article belongs to the Special Issue New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo)
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Review

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18 pages, 974 KiB  
Review
Advances in Pharmacological Approaches for Managing Hypercholesterolemia: A Comprehensive Overview of Novel Treatments
by Andrea Mormone, Giovanni Tortorella, Francesca Esposito, Alfredo Caturano, Aldo Marrone, Domenico Cozzolino, Raffaele Galiero, Raffaele Marfella, Ferdinando Carlo Sasso and Luca Rinaldi
Biomedicines 2024, 12(2), 432; https://doi.org/10.3390/biomedicines12020432 - 14 Feb 2024
Viewed by 834
Abstract
Hypercholesterolemia plays a crucial role in the formation of lipid plaques, particularly with elevated low-density lipoprotein (LDL-C) levels, which are linked to increased risks of cardiovascular disease, cerebrovascular disease, and peripheral arterial disease. Controlling blood cholesterol values, specifically reducing LDL-C, is widely recognized [...] Read more.
Hypercholesterolemia plays a crucial role in the formation of lipid plaques, particularly with elevated low-density lipoprotein (LDL-C) levels, which are linked to increased risks of cardiovascular disease, cerebrovascular disease, and peripheral arterial disease. Controlling blood cholesterol values, specifically reducing LDL-C, is widely recognized as a key modifiable risk factor for decreasing the morbidity and mortality associated with cardiovascular diseases. Historically, statins, by inhibiting the enzyme β-hydroxy β-methylglutaryl-coenzyme A (HMG)-CoA reductase, have been among the most effective drugs. However, newer non-statin agents have since been introduced into hypercholesterolemia therapy, providing a viable alternative with a favorable cost–benefit ratio. This paper aims to delve into the latest therapies, shedding light on their mechanisms of action and therapeutic benefits. Full article
(This article belongs to the Special Issue New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo)
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19 pages, 1514 KiB  
Review
Novel Insights into the Cardioprotective Effects of the Peptides of the Counter-Regulatory Renin–Angiotensin System
by Janette Alejandra Gamiño-Gutiérrez, Ivana María Terán-Hernández, Jairo Castellar-Lopez, Wendy Villamizar-Villamizar, Estefanie Osorio-Llanes, Mariali Palacios-Cruz, Wendy Rosales, Aileen Y. Chang, Luis Antonio Díaz-Ariza, María Clara Ospino and Evelyn Mendoza-Torres
Biomedicines 2024, 12(2), 255; https://doi.org/10.3390/biomedicines12020255 - 23 Jan 2024
Viewed by 899
Abstract
Currently, cardiovascular diseases are a major contributor to morbidity and mortality worldwide, having a significant negative impact on both the economy and public health. The renin–angiotensin system contributes to a high spectrum of cardiovascular disorders and is essential for maintaining normal cardiovascular homeostasis. [...] Read more.
Currently, cardiovascular diseases are a major contributor to morbidity and mortality worldwide, having a significant negative impact on both the economy and public health. The renin–angiotensin system contributes to a high spectrum of cardiovascular disorders and is essential for maintaining normal cardiovascular homeostasis. Overactivation of the classical renin–angiotensin system is one of the most important pathophysiological mechanisms in the progression of cardiovascular diseases. The counter-regulatory renin–angiotensin system is an alternate pathway which favors the synthesis of different peptides, including Angiotensin-(1-7), Angiotensin-(1-9), and Alamandine. These peptides, via the angiotensin type 2 receptor (AT2R), MasR, and MrgD, initiate multiple downstream signaling pathways that culminate in the activation of various cardioprotective mechanisms, such as decreased cardiac fibrosis, decreased myocardial hypertrophy, vasodilation, decreased blood pressure, natriuresis, and nitric oxide synthesis. These cardioprotective effects position them as therapeutic alternatives for reducing the progression of cardiovascular diseases. This review aims to show the latest findings on the cardioprotective effects of the main peptides of the counter-regulatory renin–angiotensin system. Full article
(This article belongs to the Special Issue New Advance in Cardiovascular Drugs: In Celebration of the 90th Birthday of Professor Akira Endo)
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