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Molecular Pharmacology of Cardiovascular Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 11443

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Guest Editor
Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, Cluj-Napoca, Romania
Interests: ultrasound imaging; ultrasonography; heart failure; internal medicine; cardiovascular disease; metabolic syndrome; pharmacology; cardiology; pharmacodynamics; atherosclerosis
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Special Issue Information

Dear Colleagues,

Cardiovascular diseases represent the leading cause of death in developed countries. Although there are numerous types of interventions which aim to educate people in the matters of healthy lifestyle, the large majority of cardiovascular patients require pharmacological management. The increased rhythm of technological advances permits the creation of more efficient and personalized types of pharmacological treatments.

In this Special Issue, entitled “Molecular Pharmacology of Cardiovascular Disease”, we want to present papers which deal with the newest research in the field of molecular cardiovascular pharmacology. We welcome reviews and original research papers from fundamental and clinical research addressing issues from all branches of cardiovascular pharmacology.

Dr. Stefan Cristian Vesa
Guest Editor

Manuscript Submission Information

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Keywords

  • heart failure
  • internal medicine
  • cardiovascular disease
  • metabolic syndrome
  • pharmacology
  • cardiology
  • pharmacodynamics

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Published Papers (8 papers)

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Research

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15 pages, 7446 KiB  
Article
Cardioprotective Effects of the GRK2 Inhibitor Paroxetine on Isoproterenol-Induced Cardiac Remodeling by Modulating NF-κB Mediated Prohypertrophic and Profibrotic Gene Expression
by Asma S. Alonazi, Anfal F. Bin Dayel, Danah A. Albuaijan, Alhanouf S. Bin Osfur, Fatemah M. Hakami, Shaden S. Alzayed, Ahmad R. Almotairi, Mohammad R. Khan, Hana M. Alharbi, Rehab A. Ali, Maha A. Alamin, Hanan K. Alghibiwi, Nouf M. Alrasheed and Khaled A. Alhosaini
Int. J. Mol. Sci. 2023, 24(24), 17270; https://doi.org/10.3390/ijms242417270 - 08 Dec 2023
Viewed by 906
Abstract
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart [...] Read more.
Pathological cardiac remodeling is associated with cardiovascular disease and can lead to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the hypertrophic heart. Moreover, the expression of the G-protein-coupled receptor kinase 2 (GRK2) is increased and linked to the progression of heart failure. The inhibitory effects of paroxetine on GRK2 have been established. However, its protective effect on IκBα/NFκB signaling has not been elucidated. This study investigated the cardioprotective effect of paroxetine in an animal model of cardiac hypertrophy (CH), focusing on its effect on GRK2-mediated NF-κB-regulated expression of prohypertrophic and profibrotic genes. Wistar albino rats were administered normal saline, paroxetine, or fluoxetine, followed by isoproterenol to induce CH. The cardioprotective effects of the treatments were determined by assessing cardiac injury, inflammatory biomarker levels, histopathological changes, and hypertrophic and fibrotic genes in cardiomyocytes. Paroxetine pre-treatment significantly decreased the HW/BW ratio (p < 0.001), and the expression of prohypertrophic and profibrotic genes Troponin-I (p < 0.001), BNP (p < 0.01), ANP (p < 0.001), hydroxyproline (p < 0.05), TGF-β1 (p < 0.05), and αSMA (p < 0.01) as well as inflammatory markers. It also markedly decreased pIκBα, NFκB(p105) subunit expression (p < 0.05) and phosphorylation. The findings suggest that paroxetine prevents pathological cardiac remodeling by inhibiting the GRK2-mediated IκBα/NF-κB signaling pathway. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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22 pages, 5493 KiB  
Article
The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists
by Aneta Kaczor, Joanna Knutelska, Katarzyna Kucwaj-Brysz, Małgorzata Zygmunt, Ewa Żesławska, Agata Siwek, Marek Bednarski, Sabina Podlewska, Magdalena Jastrzębska-Więsek, Wojciech Nitek, Jacek Sapa and Jadwiga Handzlik
Int. J. Mol. Sci. 2023, 24(23), 16609; https://doi.org/10.3390/ijms242316609 - 22 Nov 2023
Viewed by 690
Abstract
In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (115) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal [...] Read more.
In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (115) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 79. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α1-adrenergic receptors (α1-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α1-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α1A and α1B, was conducted. Selected compounds were tested for their activity towards two α1-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC50 < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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8 pages, 958 KiB  
Article
Galectin-3, Inflammation, and the Risk of Atrial High-Rate Episodes in Patients with Dual Chamber Pacemakers
by Gelu Radu Simu, Raluca Tomoaia, Radu Ovidiu Rosu, Gabriel Gusetu, Mihai Puiu, Gabriel Cismaru, Bogdan Caloian, Andreea Terec, Teodor Buliga, Armand Boer, Ioan Alexandru Minciuna, Gyorgy Bodizs, Dumitru Zdrenghea and Dana Pop
Int. J. Mol. Sci. 2023, 24(9), 7710; https://doi.org/10.3390/ijms24097710 - 23 Apr 2023
Cited by 1 | Viewed by 1055
Abstract
Atrial high-rate episodes (AHREs) are atrial tachyarrhythmias that are exclusively detected by cardiac implantable electronic devices (CIEDs) with an atrial lead. The objective of this study was to investigate the incidence and predictive factors for AHREs, and to evaluate the ability of inflammation [...] Read more.
Atrial high-rate episodes (AHREs) are atrial tachyarrhythmias that are exclusively detected by cardiac implantable electronic devices (CIEDs) with an atrial lead. The objective of this study was to investigate the incidence and predictive factors for AHREs, and to evaluate the ability of inflammation biomarkers to predict the occurrence of AHREs. 102 patients undergoing CIED procedure who received a dual chamber pacemaker were included. CIED interrogation was performed 1 year after the implantation procedure. Patients were divided into groups according to the occurrence of AHREs, which was the primary endpoint of the study. The mean age of the patients was of 73 ± 8.6 years and 48% were male. The incidence of AHREs was 67% at 1 year follow-up. Patients with AHREs were older, had higher left atrial indexed volume (LAVi), higher baseline galectin-3 levels (1007.5 ± 447.3 vs. 790 ± 411.7 pg/mL) and received betablockers more often, along with amiodarone and anticoagulants. Interestingly, the CHADSVASC score did not differ significantly between the two groups. A cut-off value of galectin > 990 pg/mL predicted AHREs with moderate accuracy (AUC of 0.63, 95% CI 0.52 to 0.73, p = 0.04), and this association was confirmed in the univariate regression analysis (OR 1.0012, 95% CI 1.0001 to 1.0023, p = 0.0328). However, based on the multivariate regression analysis, galectin lost its prognostic significance under the effect of LAVi, which remained the only independent predictor of AHREs (OR 1.0883, 95% CI 1.0351 to 1.1441, p = 0.0009). AHREs are common in CIEDs patients. Galectin-3 may bring additional data in the prediction of AHREs. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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21 pages, 2177 KiB  
Article
Transplacental Therapeutic Drug Monitoring in Pregnant Women with Fetal Tachyarrhythmia Using HPLC-MS/MS
by Natalia Starodubtseva, Svetlana Kindysheva, Alyona Potapova, Evgenii Kukaev, Zulfiya Khodzhaeva, Ekaterina Bockeria, Vitaliy Chagovets, Vladimir Frankevich and Gennady Sukhikh
Int. J. Mol. Sci. 2023, 24(3), 1848; https://doi.org/10.3390/ijms24031848 - 17 Jan 2023
Viewed by 1907
Abstract
Fetal arrhythmia develops in 0.1–5% of pregnancies and may cause fetal heart failure and fetal hydrops, thus increasing fetal, neonatal, and infant mortality. The timely initiation of transplacental antiarrhythmic therapy (ART) promotes the conversion of fetal tachycardia to sinus rhythm and the regression [...] Read more.
Fetal arrhythmia develops in 0.1–5% of pregnancies and may cause fetal heart failure and fetal hydrops, thus increasing fetal, neonatal, and infant mortality. The timely initiation of transplacental antiarrhythmic therapy (ART) promotes the conversion of fetal tachycardia to sinus rhythm and the regression of the concomitant non-immune fetal hydrops. The optimal treatment regimen search for the fetus with tachyarrhythmia is still of high value. Polymorphisms of these genes determines the individual features of the drug pharmacokinetics. The aim of this study was to study the pharmacokinetics of transplacental anti-arrhythmic drugs in the fetal therapy of arrhythmias using HPLC-MS/MS, as well as to assess the effect of the multidrug-resistance gene ABCB1 3435C > T polymorphism on the efficacy and maternal/fetal complications of digoxin treatment. The predisposition to a decrease in the bioavailability of the digoxin in patients with a homozygous variant of the CC polymorphism showed a probable association with the development of ART side effects. A pronounced decrease in heart rate in women with the 3435TT allele of the ABCB1 gene was found. The homozygous TT variant in the fetus showed a probable association with an earlier response to ART and rhythm disruptions on the digoxin dosage reduction. high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) methods for digoxin and sotalol therapeutic drug monitoring in blood plasma, amniotic fluid, and urine were developed. The digoxin and sotalol concentrations were determined in the plasma blood, urine, and amniotic fluid of 30 pregnant women at four time points (from the beginning of the transplacental antiarrhythmic therapy to delivery) and the plasma cord blood of 30 newborns. A high degree of correlation between the level of digoxin and sotalol in maternal and cord blood was found. The ratio of digoxin and sotalol in cord blood to maternal blood was 0.35 (0.27 and 0.46) and 1.0 (0.97 and 1.07), accordingly. The digoxin concentration in the blood of the fetus at the moment of the first rhythm recovery episode, 0.58 (0.46, 0.8) ng/mL, was below the therapeutic interval. This confirms the almost complete transplacental transfer of sotalol and the significant limitation in the case of digoxin. Previously, ABCB1/P-glycoprotein had been shown to limit fetal exposure to drugs. Further studies (including multicenter ones) to clarify the genetic features of the transplacental pharmacokinetics of antiarrhythmic drugs are needed. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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Review

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16 pages, 1068 KiB  
Review
Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension
by Riccardo Sarzani, Francesco Spannella, Chiara Di Pentima, Federico Giulietti, Matteo Landolfo and Massimiliano Allevi
Int. J. Mol. Sci. 2024, 25(1), 328; https://doi.org/10.3390/ijms25010328 - 26 Dec 2023
Cited by 1 | Viewed by 1536
Abstract
Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown [...] Read more.
Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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19 pages, 1289 KiB  
Review
PDE4 Phosphodiesterases in Cardiovascular Diseases: Key Pathophysiological Players and Potential Therapeutic Targets
by Lídia Puertas-Umbert, Judith Alonso, Leif Hove-Madsen, José Martínez-González and Cristina Rodríguez
Int. J. Mol. Sci. 2023, 24(23), 17017; https://doi.org/10.3390/ijms242317017 - 30 Nov 2023
Cited by 1 | Viewed by 1075
Abstract
3′,5′-cyclic adenosine monophosphate (cAMP) is a second messenger critically involved in the control of a myriad of processes with significant implications for vascular and cardiac cell function. The temporal and spatial compartmentalization of cAMP is governed by the activity of phosphodiesterases (PDEs), a [...] Read more.
3′,5′-cyclic adenosine monophosphate (cAMP) is a second messenger critically involved in the control of a myriad of processes with significant implications for vascular and cardiac cell function. The temporal and spatial compartmentalization of cAMP is governed by the activity of phosphodiesterases (PDEs), a superfamily of enzymes responsible for the hydrolysis of cyclic nucleotides. Through the fine-tuning of cAMP signaling, PDE4 enzymes could play an important role in cardiac hypertrophy and arrhythmogenesis, while it decisively influences vascular homeostasis through the control of vascular smooth muscle cell proliferation, migration, differentiation and contraction, as well as regulating endothelial permeability, angiogenesis, monocyte/macrophage activation and cardiomyocyte function. This review summarizes the current knowledge and recent advances in understanding the contribution of the PDE4 subfamily to cardiovascular function and underscores the intricate challenges associated with targeting PDE4 enzymes as a therapeutic strategy for the management of cardiovascular diseases. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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19 pages, 1702 KiB  
Review
Insights into Endothelin Receptors in Pulmonary Hypertension
by Ruiqi Liu, Tianyi Yuan, Ranran Wang, Difei Gong, Shoubao Wang, Guanhua Du and Lianhua Fang
Int. J. Mol. Sci. 2023, 24(12), 10206; https://doi.org/10.3390/ijms241210206 - 16 Jun 2023
Cited by 1 | Viewed by 1263
Abstract
Pulmonary hypertension (PH) is a disease which affects the cardiopulmonary system; it is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as measured by right heart catheterization at rest, and is caused by complex and diverse mechanisms. In response to [...] Read more.
Pulmonary hypertension (PH) is a disease which affects the cardiopulmonary system; it is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg as measured by right heart catheterization at rest, and is caused by complex and diverse mechanisms. In response to stimuli such as hypoxia and ischemia, the expression and synthesis of endothelin (ET) increase, leading to the activation of various signaling pathways downstream of it and producing effects such as the induction of abnormal vascular proliferation during the development of the disease. This paper reviews the regulation of endothelin receptors and their pathways in normal physiological processes and disease processes, and describes the mechanistic roles of ET receptor antagonists that are currently approved and used in clinical studies. Current clinical researches on ET are focused on the development of multi-target combinations and novel delivery methods to improve efficacy and patient compliance while reducing side effects. In this review, future research directions and trends of ET targets are described, including monotherapy and precision medicine. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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38 pages, 2654 KiB  
Review
Natural Monoterpenes as Potential Therapeutic Agents against Atherosclerosis
by Jing Yang, Chao Zhong and Jun Yu
Int. J. Mol. Sci. 2023, 24(3), 2429; https://doi.org/10.3390/ijms24032429 - 26 Jan 2023
Cited by 5 | Viewed by 2042
Abstract
Traditional herbal medicines based on natural products play a pivotal role in preventing and managing atherosclerotic diseases, which are among the leading causes of death globally. Monoterpenes are a large class of naturally occurring compounds commonly found in many aromatic and medicinal plants. [...] Read more.
Traditional herbal medicines based on natural products play a pivotal role in preventing and managing atherosclerotic diseases, which are among the leading causes of death globally. Monoterpenes are a large class of naturally occurring compounds commonly found in many aromatic and medicinal plants. Emerging evidence has shown that monoterpenes have many biological properties, including cardioprotective effects. Remarkably, an increasing number of studies have demonstrated the therapeutic potential of natural monoterpenes to protect against the pathogenesis of atherosclerosis. These findings shed light on developing novel effective antiatherogenic drugs from these compounds. Herein, we provide an overview of natural monoterpenes’ effects on atherogenesis and the underlying mechanisms. Monoterpenes have pleiotropic and multitargeted pharmacological properties by interacting with various cell types and intracellular molecular pathways involved in atherogenesis. These properties confer remarkable advantages in managing atherosclerosis, which has been recognized as a multifaceted vascular disease. We also discuss limitations in the potential clinical application of monoterpenes as therapeutic agents against atherosclerosis. We propose perspectives to give new insights into future preclinical research and clinical practice regarding natural monoterpenes. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease)
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