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Molecular Pharmacology and Interventions in Cardiovascular Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 9821

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Dr. Magdalena Zabielska-Kaczorowska

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Guest Editor

Department of Physiology, Medical University of Gdansk, 80-210 Gdansk, Poland
Interests: heart metabolism; purine metabolism; ischemic heart disease; cardioplegia; myocardial ischemia and infarction; cardiac energetics
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Special Issue Information

Dear Colleagues,

The prevalence of cardiovascular diseases, which are complex and multifunctional, rises as the mean age of the population increases. The size of the myocardial infarction remains a crucial therapeutic target, because it correlates with heart failure and mortality. Efforts are being directed towards the development of novel drugs via the physiochemical modification of drug molecules and the design and synthesis of new drugs, with an emphasis on drug delivery, controlled drug release, and the targeting of drugs to the site of action in order to enhance the therapeutic effect.

While numerous pre-clinical studies have revealed that certain pharmacologic agents and therapeutic maneuvers reduce the myocardial infarction size more significantly than reperfusion alone, very few of these therapies have translated into successful clinical trials or standard clinical application. The optimization of pharmacologic agents is critical to the development of diagnostic, treatment, and preventive strategies in the cardiology field. It is essential to promote the endogenous regeneration of the heart in order to improve the prognosis of patients with cardiac injury and to find effective therapeutic strategies for it.

This Special Issue focuses on the role of cardiovascular pharmacology and interventions in cardiac injury, aiming to elucidate pharmacologic strategies that may be employed to promote heart repair after cardiac injury.

Dr. Magdalena Zabielska-Kaczorowska
Guest Editor

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Keywords

cardiovascular pharmacology
cardiovascular interventions
cardioprotection
myocardial ischemia and infarction
heart failure

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Published Papers (8 papers)

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Research

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15 pages, 5367 KiB

Open AccessArticle

Prolonged Extracorporeal Circulation Leads to Inflammation and Higher Expression of Mediators of Vascular Permeability Through Activation of STAT3 Signaling Pathway in Macrophages

by Jana Luecht, Camila Pauli, Raphael Seiler, Alexa-Leona Herre, Liliya Brankova, Felix Berger, Katharina R. L. Schmitt and Giang Tong

Int. J. Mol. Sci. 2024, 25(22), 12398; https://doi.org/10.3390/ijms252212398 - 19 Nov 2024

Viewed by 247

Abstract

Congenital heart defects (CHDs) are one of the most common congenital malformations and often require heart surgery with cardiopulmonary bypass (CPB). Children undergoing cardiac surgery with CPB are especially at greater risk of post-operative complications due to a systemic inflammatory response caused by innate inflammatory mediators. However, the pathophysiological response is not fully understood and warrants further investigation. Therefore, we investigated the inflammatory response in macrophages initiated by peri-operative serum samples obtained from patients with CHD undergoing CPB cardiac surgery. Human differentiated THP-1 macrophages were pretreated with Stattic, a STAT3 (Tyr705) inhibitor, before stimulation with serum samples. STAT3 and NF-κB activation were investigated via a Western blot, IL-1β, TNFα, IL-10, mediators for vascular permeability (VEGF-A, ICAM), and SOCS3 gene expressions via RT-qPCR. CPB induced an inflammatory response in macrophages via the activation of the STAT3 but not NF-κB signaling pathway. Longer duration on the CPB correlated with increased cytokine, VEGF, and ICAM expressions, relative to individual pre-operation levels. Patients that did not require CPB showed no significant immune response. Pretreatment with Stattic significantly attenuated all inflammatory mediators investigated except for TNFα in the macrophages. CPB induces an increased expression of cytokines and mediators of vascular permeability via the activation of STAT3 by IL-6 and IL-8 in the serum samples. Stattic attenuates all mediators investigated but promotes TNFα expression. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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10 pages, 4206 KiB

Open AccessArticle

Synthetic Flavonoid 3,7-Dihydroxy-Isoflav-3-Ene (DHIF) Reduces In-Stent Restenosis in an Atherosclerotic Watanabe Heritable Hyperlipidemic Rabbit Stent Model

by Jarkko P. Hytönen, Olli Leppänen, Jouni Taavitsainen and Seppo Ylä-Herttuala

Int. J. Mol. Sci. 2024, 25(21), 11530; https://doi.org/10.3390/ijms252111530 - 27 Oct 2024

Viewed by 489

Abstract

Inflammation is a major component of the pathogenesis of atherosclerosis and the formation of in-stent restenosis (ISR). A novel flavonoid, DHIF, attenuates reactive oxygen species and nf-κB signaling and has potential to limit ISR via antioxidant action. While current drug eluting stents (DESs) perform well in clinical practice, new therapies to prevent ISR without dependance on cytotoxic drugs are warranted. Our objective was to test whether DHIF reduces ISR in a hyperlipidemic rabbit aorta model of ISR via attenuated inflammatory responses. WHHL rabbit aortas (n = 24) were denuded. Six weeks after injury, stents were implanted into the denuded aortas. DHIF was dissolved in carboxymethyl cellulose (CMC) and administered orally with two doses. CMC served as a control. The animals were sacrificed six weeks after stenting. ISR was evaluated from stent histomorphometry and immunohistology was used to assess the inflammatory and antiproliferative effects of the treatment. ISR was reduced from 20.9 ± 3.0% in controls to 15.2 ± 2.4% (p = 0.0009) and 16.4 ± 2.1% (p = 0.004) in the low- and high-dose groups, respectively. The neointimal area covered by macrophages was 32 ± 9.3% in the controls, 17.2 ± 5.9% (p = 0.005) in the low-dose group and 19.4 ± 7.9% (p = 0.008) in the high-dose group. DHIF significantly reduces ISR and local inflammation in stented arterial regions and could be used to reduce ISR when bare metal stents are used. Targeting local inflammation in the arterial wall may provide a way to reduce ISR in a clinical setting and further studies are warranted. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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18 pages, 14180 KiB

Open AccessArticle

A Novel Strategy for the Treatment of Aneurysms: Inhibition of MMP-9 Activity through the Delivery of TIMP-1 Encoding Synthetic mRNA into Arteries

by Sonia Golombek, Isabelle Doll, Louisa Kaufmann, Mario Lescan, Christian Schlensak and Meltem Avci-Adali

Int. J. Mol. Sci. 2024, 25(12), 6599; https://doi.org/10.3390/ijms25126599 - 15 Jun 2024

Viewed by 1175

Abstract

Aneurysms pose life-threatening risks due to the dilatation of the arteries and carry a high risk of rupture. Despite continuous research efforts, there are still no satisfactory or clinically effective pharmaceutical treatments for this condition. Accelerated inflammatory processes during aneurysm development lead to increased levels of matrix metalloproteinases (MMPs) and destabilization of the vessel wall through the degradation of the structural components of the extracellular matrix (ECM), mainly collagen and elastin. Tissue inhibitors of metalloproteinases (TIMPs) directly regulate MMP activity and consequently inhibit ECM proteolysis. In this work, the synthesis of TIMP-1 protein was increased by the exogenous delivery of synthetic TIMP-1 encoding mRNA into aortic vessel tissue in an attempt to inhibit MMP-9. In vitro, TIMP-1 mRNA transfection resulted in significantly increased TIMP-1 protein expression in various cells. The functionality of the expressed protein was evaluated in an appropriate ex vivo aortic vessel model. Decreased MMP-9 activity was detected using in situ zymography 24 h and 48 h post microinjection of 5 µg TIMP-1 mRNA into the aortic vessel wall. These results suggest that TIMP-1 mRNA administration is a promising approach for the treatment of aneurysms. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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14 pages, 4544 KiB

Open AccessArticle

Does Cell-Type-Specific Silencing of Monoamine Oxidase B Interfere with the Development of Right Ventricle (RV) Hypertrophy or Right Ventricle Failure in Pulmonary Hypertension?

by Paulin Brosinsky, Jacqueline Heger, Akylbek Sydykov, Astrid Weiss, Stephan Klatt, Laureen Czech, Simone Kraut, Ralph Theo Schermuly, Klaus-Dieter Schlüter and Rainer Schulz

Int. J. Mol. Sci. 2024, 25(11), 6212; https://doi.org/10.3390/ijms25116212 - 5 Jun 2024

Cited by 2 | Viewed by 799

Abstract

Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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12 pages, 1784 KiB

Open AccessArticle

Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome

by Irene Valdivia Callejon, Lucia Buccioli, Jarl Bastianen, Jolien Schippers, Aline Verstraeten, Ilse Luyckx, Silke Peeters, A. H. Jan Danser, Roland R. J. Van Kimmenade, Josephina Meester and Bart Loeys

Int. J. Mol. Sci. 2024, 25(9), 5025; https://doi.org/10.3390/ijms25095025 - 4 May 2024

Cited by 1 | Viewed by 1731

Abstract

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and β-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of β-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a β-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1^C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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Review

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34 pages, 3381 KiB

Open AccessReview

The Interaction of Vasopressin with Hormones of the Hypothalamo–Pituitary–Adrenal Axis: The Significance for Therapeutic Strategies in Cardiovascular and Metabolic Diseases

by Ewa Szczepanska-Sadowska, Katarzyna Czarzasta, Wiktor Bogacki-Rychlik and Michał Kowara

Int. J. Mol. Sci. 2024, 25(13), 7394; https://doi.org/10.3390/ijms25137394 - 5 Jul 2024

Viewed by 1233

Abstract

A large body of evidence indicates that vasopressin (AVP) and steroid hormones are frequently secreted together and closely cooperate in the regulation of blood pressure, metabolism, water–electrolyte balance, and behavior, thereby securing survival and the comfort of life. Vasopressin cooperates with hormones of the hypothalamo–pituitary–adrenal axis (HPA) at several levels through regulation of the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and multiple steroid hormones, as well as through interactions with steroids in the target organs. These interactions are facilitated by positive and negative feedback between specific components of the HPA. Altogether, AVP and the HPA cooperate closely as a coordinated functional AVP-HPA system. It has been shown that cooperation between AVP and steroid hormones may be affected by cellular stress combined with hypoxia, and by metabolic, cardiovascular, and respiratory disorders; neurogenic stress; and inflammation. Growing evidence indicates that central and peripheral interactions between AVP and steroid hormones are reprogrammed in cardiovascular and metabolic diseases and that these rearrangements exert either beneficial or harmful effects. The present review highlights specific mechanisms of the interactions between AVP and steroids at cellular and systemic levels and analyses the consequences of the inappropriate cooperation of various components of the AVP-HPA system for the pathogenesis of cardiovascular and metabolic diseases. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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21 pages, 2528 KiB

Open AccessReview

Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review

by Antonio da Silva Menezes Junior, Ana Luísa Guedes de França-e-Silva, Henrique Lima de Oliveira, Khissya Beatryz Alves de Lima, Iane de Oliveira Pires Porto, Thays Millena Alves Pedroso, Daniela de Melo e Silva and Aguinaldo F. Freitas, Jr.

Int. J. Mol. Sci. 2024, 25(11), 5855; https://doi.org/10.3390/ijms25115855 - 28 May 2024

Cited by 1 | Viewed by 1534

Abstract

Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using “MESH terms”. Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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15 pages, 748 KiB

Open AccessReview

Therapies for Cirrhotic Cardiomyopathy: Current Perspectives and Future Possibilities

by Hongqun Liu, Daegon Ryu, Sangyoun Hwang and Samuel S. Lee

Int. J. Mol. Sci. 2024, 25(11), 5849; https://doi.org/10.3390/ijms25115849 - 28 May 2024

Viewed by 1523

Abstract

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Interventions in Cardiovascular Disease)

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