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Molecular mechanisms and targets of right ventricular fibrosis in pulmonary hypertension

PHARMACOLOGY & THERAPEUTICS (2023)

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1,8-Cineole ameliorates right ventricle dysfunction associated with pulmonary arterial hypertension by restoring connexin43 and mitochondrial homeostasis

Jorge M. Alves-Silva et al.

Summary: For the first time, this study reveals a novel cardiac-specific therapeutic approach for improving the prognosis of Pulmonary Arterial Hypertension (PAH). The findings suggest that 1,8-cineole can alleviate cardiac hypertrophy and enhance heart function by preserving cardiac cell-to-cell communication and bioenergetics.

PHARMACOLOGICAL RESEARCH (2022)

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Article Biotechnology & Applied Microbiology

Chronic Sigma 1 receptor activation alleviates right ventricular dysfunction secondary to pulmonary arterial hypertension

Yazhou Sun et al.

Summary: This study aimed to investigate the effects of S1R on right ventricular dysfunction secondary to pulmonary arterial hypertension. The results showed that S1R activation can improve right ventricular dysfunction and ameliorate right ventricular structural remodeling, without affecting pulmonary artery pressure.

BIOENGINEERED (2022)

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Article Cardiac & Cardiovascular Systems

Celastrol attenuates the remodeling of pulmonary vascular and right ventricular in monocrotaline-induced pulmonary arterial hypertension in rats

Huayang Li et al.

Summary: Pulmonary arterial hypertension is a progressive angio-proliferative disease with high mortality rates and unsatisfactory therapeutic options. Treatment with celastrol in rats with pulmonary arterial hypertension showed improvements in right ventricular function, attenuation of right ventricular and pulmonary vascular remodeling, and inhibition of human pulmonary artery smooth cells proliferation under hypoxia, possibly through suppression of the NF-ΚB signaling pathway.

CARDIOVASCULAR DIAGNOSIS AND THERAPY (2022)

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Review Cardiac & Cardiovascular Systems

Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic Target

Katharina Schimmel et al.

Summary: Myocardial fibrosis is a process of extracellular matrix remodeling in response to cardiac stress. It can be classified into replacement fibrosis and reactive fibrosis. Reactive fibrosis develops over time in chronic pressure overload and affects the function of the left or right ventricle. Reactive fibrosis in the left ventricle is associated with the development and progression of heart failure, while reactive fibrosis in the right ventricle is common in conditions such as pulmonary arterial hypertension. Understanding the differences and common characteristics of extracellular matrix remodeling in the left and right ventricles under pressure overload is crucial for developing new approaches to treat heart disease.

FRONTIERS IN CARDIOVASCULAR MEDICINE (2022)

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Article Critical Care Medicine

Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension

Ruaa Al-Qazazi et al.

Summary: This study evaluates the contribution of NLRP3 inflammasome activation in RV macrophages to PAH RVF. The results show that NLRP3-macrophage activation occurs in both preclinical PAH models and PAH patients. Inhibiting NLRP3 signaling improves RV function, suggesting a new therapeutic paradigm for PAH RVF.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2022)

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Article Biochemistry & Molecular Biology

Proteomic and Metabolomic Analyses of Right Ventricular Failure due to Pulmonary Arterial Hypertension

Xiaohan Qin et al.

Summary: In this study, myocardial proteomics combined with metabolomics were used to investigate the pathophysiological changes of right ventricular remodeling in a monocrotaline-induced pulmonary arterial hypertension (PAH) rat model. The results revealed that elevated intracellular Ca2+ concentrations and inflammation may contribute to myocardial proliferation and contraction, which are beneficial for maintaining the compensated state of the right ventricle. However, in the right ventricular failure stage, ferroptosis, mitochondrial metabolic shift, and insulin resistance play significant roles.

FRONTIERS IN MOLECULAR BIOSCIENCES (2022)

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Review Cardiac & Cardiovascular Systems

Integrins in cardiac fibrosis

Ruoshui Li et al.

Summary: Integrins, a family of surface receptors, play a role in sensing mechanical stress and changes in the matrix environment, and are involved in the regulation of fibrosis. In myocardial fibrosis, integrins are implicated in fibrogenic conversion of cardiac fibroblasts and may mediate recruitment and activation of fibrogenic macrophages. The role of integrins in cardiac fibrosis is dependent on the underlying pathologic condition and further research is needed to fully understand their involvement.

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY (2022)

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Article Cardiac & Cardiovascular Systems

The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease

Roddy Hiram et al.

Summary: The study found that the inflammation-resolution enhancing molecule RvD1 can prevent atrial arrhythmogenic remodeling in experimental RHD by suppressing inflammatory signaling and fibrotic/electrical remodeling.

CARDIOVASCULAR RESEARCH (2021)

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Article Cardiac & Cardiovascular Systems

Acetazolamide Improves Right Ventricular Function and Metabolic Gene Dysregulation in Experimental Pulmonary Arterial Hypertension

Fotios Spyropoulos et al.

Summary: In a severe PAH rat model, treatment with acetazolamide improves right ventricular dysfunction caused by pulmonary arterial hypertension, modulating metabolic balance and potentially preventing or alleviating right ventricular hypertrophy and pathological fibrosis.

FRONTIERS IN CARDIOVASCULAR MEDICINE (2021)

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Article Hematology

Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A)

Ryo Kurosawa et al.

Summary: Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, leading to right ventricular failure. Bsg and CyPA play crucial roles in exacerbating RV dysfunction, while celastrol has potential as a novel drug for PH and RV failure by suppressing Bsg and CyPA.

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY (2021)

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Article Cardiac & Cardiovascular Systems

BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats

Ana Paula Ferraz et al.

Summary: The selective BKCa channel opener (compound X) showed significant therapeutic efficacy in rats with MCT-induced PAH, improving hemodynamic parameters and preventing maladaptive RV remodeling.

CARDIOVASCULAR DRUGS AND THERAPY (2021)

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Article Cardiac & Cardiovascular Systems

Seamless Genetic Recording of Transiently Activated Mesenchymal Gene Expression in Endothelial Cells During Cardiac Fibrosis

Shaohua Zhang et al.

Summary: The study reveals that during cardiac development, cardiac ECs can transdifferentiate into mesenchymal cells through EndoMT but do not contribute to myofibroblasts or express known mesenchymal genes transiently during fibrosis in the adult heart. Resident fibroblasts are the major contributors to cardiac fibrosis by activating mesenchymal gene expression.

CIRCULATION (2021)

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Article Cell Biology

Diverse origins and activation of fibroblasts in cardiac fibrosis

Preetinder K. Aujla et al.

Summary: Cardiac fibroblasts are a heterogeneous cell population and play a crucial role in synthesizing the extracellular matrix (ECM). Various cell types can transform into activated myofibroblasts, leading to accelerated fibrotic response. Multiple molecules stimulate the activation of myofibroblasts, exacerbating fibrosis in the myocardium.

CELLULAR SIGNALLING (2021)

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Article Cardiac & Cardiovascular Systems

Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension Identification and Validation of Epithelial-to-Mesenchymal Transition in Human Right Ventricular Failure

John F. Park et al.

Summary: RV failure in monocrotaline and Sugen with hypoxia models showed similar gene expressions and biological pathways, with significant enrichment in genes related to epithelial-to-mesenchymal transition, inflammation, and metabolism. Human RV tissue from PAH-induced RV failure patients exhibited notable fibrosis, endothelial-to-mesenchymal transition, and elevated expression of cellular communication network factor 2 in perivascular areas compared to normal RV.

CIRCULATION-HEART FAILURE (2021)

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Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload

Yan Zou et al.

Summary: Progressive cardiac fibrosis is accelerated by elevated serum levels of Wnt5a and Wnt11 in hypertension patients, leading to diastolic dysfunction. Pressure overload increases the secretion of Wnt5a and Wnt11 from cardiomyocytes and cardiac fibroblasts, promoting cardiac fibrosis through the activation of FZD5 and EGFR crosstalk.

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Improving Right Ventricular Function by Increasing BMP Signaling with FK506

Mario Boehm et al.

Summary: The study shows that increasing cardiac BMP signaling with FK506 improves RV structure and function independently from its previously described beneficial effects on pulmonary vascular remodeling.

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Sotatercept for the Treatment of Pulmonary Arterial Hypertension

Marc Humbert et al.

Summary: In this study, patients with pulmonary arterial hypertension receiving Sotatercept treatment showed a significant reduction in pulmonary vascular resistance at 24 weeks, with both Sotatercept groups performing better than the placebo group.

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Review Cell Biology

Cardiac Fibrosis: Key Role of Integrins in Cardiac Homeostasis and Remodeling

Patrick B. Meagher et al.

Summary: Cardiac fibrosis is a common occurrence in the progression of heart failure, impacting all chambers of the heart. Despite the lack of targeted antifibrotic strategies, integrins play a crucial role in mechano-transduced cardiac fibrosis, both initiating the fibrotic response and modulating fibrosis across the various heart chambers.

CELLS (2021)

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Article Medicine, Research & Experimental

α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension

Alexander Vang et al.

Summary: The study shows that increased collagen content and ACh expression in RV tissue of PH patients. In an experimental rat model of PH, RV fibrosis and dysfunction are associated with increased ACh and alpha 7 nAChR expression. Activation of alpha 7 nAChR leads to ventricular fibroblast proliferation and collagen content increase. Pharmacological antagonism of nAChR decreases RV collagen content and improves RV function in the PH model.

JCI INSIGHT (2021)

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Article Biochemistry & Molecular Biology

WNT/β-Catenin Signaling Promotes TGF-β-Mediated Activation of Human Cardiac Fibroblasts by Enhancing IL-11 Production

Edyta Dzialo et al.

Summary: The study revealed that WNT/beta-catenin signaling promotes the transition of cardiac fibroblasts to myofibroblasts by enhancing IL-11 production in TGF-beta-mediated pathways, while non-canonical WNT5a co-activation suppressed TGF-beta-induced collagen I production.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Cardiac & Cardiovascular Systems

Quercetin, Perillyl Alcohol, and Berberine Ameliorate Right Ventricular Disorders in Experimental Pulmonary Arterial Hypertension: Effects on miR-204, miR-27a, Fibrotic, Apoptotic, and Inflammatory Factors

Soodeh Rajabi et al.

Summary: The plant derivatives, perillyl alcohol (PA), quercetin (QS), and berberine (BBR), were found to improve ventricular disorders in rats with PAH by decreasing inflammation and apoptosis, and increasing the antioxidant-to-oxidant ratio.

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY (2021)

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Review Radiology, Nuclear Medicine & Medical Imaging

Myocardial T1-mapping and extracellular volume in pulmonary arterial hypertension: A systematic review and meta-analysis

Samer Alabed et al.

Summary: Elevated T1 mapping and ECV values were found in patients with pulmonary arterial hypertension (PAH), especially at the RV insertion points. These values were higher than those in cardiomyopathies and were associated with poor right ventricular function and dilatation.

MAGNETIC RESONANCE IMAGING (2021)

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Pirfenidone in heart failure with preserved ejection fraction: a randomized phase 2 trial

Gavin A. Lewis et al.

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NATURE MEDICINE (2021)

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An Insight on Multicentric Signaling of Angiotensin II in Cardiovascular system: A Recent Update

Kanika Verma et al.

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FRONTIERS IN PHARMACOLOGY (2021)

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Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury

Duncan C. Humphries et al.

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Hitoshi Kurose

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SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: A systematic review and meta-analysis

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Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension

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Pressure overload induced right ventricular remodeling is not attenuated by the anti-fibrotic agent pirfenidone

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Transient receptor potential vanilloid-3 (TRPV3) activation plays a central role in cardiac fibrosis induced by pressure overload in rats via TGF-β1 pathway

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CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload

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Iloprost reverses established fibrosis in experimental right ventricular failure

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Bisoprolol Delays Progression Towards Right Heart Failure in Experimental Pulmonary Hypertension

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Suppression of Histone Deacetylases Worsens Right Ventricular Dysfunction after Pulmonary Artery Banding in Rats

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Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure

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Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction

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Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts

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WISP1, a Pro-mitogenic, Pro-survival Factor, Mediates Tumor Necrosis Factor-α (TNF-α)-stimulated Cardiac Fibroblast Proliferation but Inhibits TNF-α-induced Cardiomyocyte Death

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Pulmonary embolism causes endomyocarditis in the human heart

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IL-1β stimulates rat cardiac fibroblast migration via MAP kinase pathways

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Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice

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Transforming growth factor-β induces endothelin-1 expression through activation of the smad signaling pathway

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Profibrotic effects of endothelin-1 via the ETA receptor in cultured human cardiac fibroblasts

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Tumor necrosis factor-α-induced AT1 receptor upregulation enhances angiotensin II-mediated cardiac fibroblast responses that favor fibrosis

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β-adrenergic receptor-mediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal-regulated kinases

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β-adrenergic stimulation of rat cardiac fibroblasts promotes protein synthesis via the activation of phosphatidylinositol 3-kinase

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Identification of novel TGF-β/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach

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Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb)

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