Excitation-contraction coupling and relaxation alteration in right ventricular remodelling caused by pulmonary arterial hypertension

Antigny, Fabrice; Mercier, Olaf; Humbert, Marc; Sabourin, Jessica

doi:10.1016/j.acvd.2019.10.009

Cited by 19 publications

(16 citation statements)

References 104 publications

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“…RV remodeling and dysfunction in MCT-PH rats have been often associated with maladaptive RV (reduction in exercise capacity, reduction in RV function, capillary rarefaction, RV inflammation). In CH-PH rats, the pulmonary arterial medial hypertrophy leads to elevated RVS.P and RV hypertrophy without RV failure [ 30 ]. In the present study, we confirmed that MCT exposure induces severe PH in rats with maladaptive RV while rats exposed to CH develop severe PH with adaptive RV.…”

Section: Discussionmentioning

confidence: 99%

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure

Hautbergue

Antigny

Boët

et al. 2021

Cells

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Introduction: Over time and despite optimal medical management of patients with pulmonary hypertension (PH), the right ventricle (RV) function deteriorates from an adaptive to maladaptive phenotype, leading to RV failure (RVF). Although RV function is well recognized as a prognostic factor of PH, no predictive factor of RVF episodes has been elucidated so far. We hypothesized that determining RV metabolic alterations could help to understand the mechanism link to the deterioration of RV function as well as help to identify new biomarkers of RV failure. Methods: In the current study, we aimed to characterize the metabolic reprogramming associated with the RV remodeling phenotype during experimental PH induced by chronic-hypoxia-(CH) exposure or monocrotaline-(MCT) exposure in rats. Three weeks after PH initiation, we hemodynamically characterized PH (echocardiography and RV catheterization), and then we used an untargeted metabolomics approach based on liquid chromatography coupled to high-resolution mass spectrometry to analyze RV and LV tissues in addition to plasma samples from MCT-PH and CH-PH rat models. Results: CH exposure induced adaptive RV phenotype as opposed to MCT exposure which induced maladaptive RV phenotype. We found that predominant alterations of arginine, pyrimidine, purine, and tryptophan metabolic pathways were detected on the heart (LV+RV) and plasma samples regardless of the PH model. Acetylspermidine, putrescine, guanidinoacetate RV biopsy levels, and cytosine, deoxycytidine, deoxyuridine, and plasmatic thymidine levels were correlated to RV function in the CH-PH model. It was less likely correlated in the MCT model. These pathways are well described to regulate cell proliferation, cell hypertrophy, and cardioprotection. These findings open novel research perspectives to find biomarkers for early detection of RV failure in PH.

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Section: Discussionmentioning

confidence: 99%

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure

Hautbergue

Antigny

Boët

et al. 2021

Cells

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“…The rats were either healthy (CONT, n = 9) or treated by monocrotaline to induce pulmonary hypertension followed by right ventricular hypertrophy and heart failure (MCT, n = 9) as described in detail elsewhere 21 . Briefly, a single injection of the pyrrolizidine alkaloid monocrotaline causes obliterating vasculitis of lung arterioles 47 and triggers endothelial dysfunction, pulmonary vascular remodelling and metabolic abnormalities in the pulmonary vasculature, 48 which leads to decompensated pulmonary hypertension. The right ventricle develops chronically elevated pressure which causes hypertrophic remodelling with elevated right ventricular fibrosis and finally the heart failure 49 .…”

Section: Methodsmentioning

confidence: 99%

The use of Ca‐transient to evaluate Ca²⁺ utilization by myofilaments in living cardiac muscle

Lookin

2020

Clin Exp Pharma Physio

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The myocardial contraction is tightly regulated by the Ca 2+-activation of myofilaments. Thin filaments contain troponin subunit (TnC) which binds Ca 2+ ions thereby allowing interfilament interaction. 1-3 The length (preload)-dependent change in Ca 2+ utilization by myofilaments constitutes one of the important regulatory mechanism in the myocardium-the Frank-Starling Mechanism. 1,4-7 This mechanism is substantially downgraded in the myocardium with troponin subunit mutations 8,9 or with impaired Ca 2+ homeostasis, eg in heart failure. 10-12 There are limited ways to measure the kinetics of Ca 2+ utilization by myofilaments in a direct manner. Skinned tissue is widely used to control and manipulate the levels of Ca 2+ activation of myofilaments

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“…We also found that ABCC8 mRNA expression is decreased in the RV from PAH patients and MCT-PH rats [ 80 ], but that KCNJ11 mRNA expression is unchanged in the RV from PAH patients. In addition, Kcnj11 mRNA expression is decreased in rat hearts and in H9c2 cells under hypoxia conditions [ 101 ].The reduction of ABCC8 expression in the RV from PAH patients and MCT-PH rats may contribute to abnormal PH-RV cardiomyocyte excitability, contractility, and metabolism [ 43 ].…”

Section: Atp Binding Cassette Subfamily C Member 8 (Abcc8)mentioning

confidence: 99%

“…KCNK3 is expressed in several cell types, including heart cells, lung cells, PASMCs, and PAECs [ 13 , 43 ]. Patch-clamp recording has demonstrated that KCNK3 is functionally expressed in cultured human PASMCs [ 30 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…At the cardiac level, KCNK3 is expressed in atria, ventricular tissues, and heart-conducting tissues in humans, mice, and rats [ 21 , 43 , 45 ]. Through whole-cell patch-clamp recordings, we found that KCNK3 is functionally expressed in adult rat RV cardiomyocytes, contributing to RV cardiomyocyte excitability (Em and action potential repolarization) [ 20 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

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Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

et al. 2020

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Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic predisposition, epigenetic factors, and environmental factors (drugs, toxins, viruses, hypoxia, and inflammation), which contribute to the initiation or development of irreversible remodeling of the pulmonary vessels. The recent identification of loss-of-function mutations in KCNK3 (KCNK3 or TASK-1) and ABCC8 (SUR1), or gain-of-function mutations in ABCC9 (SUR2), as well as polymorphisms in KCNA5 (Kv1.5), which encode two potassium (K+) channels and two K+ channel regulatory subunits, has revived the interest of ion channels in PAH. This review focuses on KCNK3, SUR1, SUR2, and Kv1.5 channels in pulmonary vasculature and discusses their pathophysiological contribution to and therapeutic potential in PAH.

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Excitation-contraction coupling and relaxation alteration in right ventricular remodelling caused by pulmonary arterial hypertension

Cited by 19 publications

References 104 publications

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure

The use of Ca‐transient to evaluate Ca²⁺ utilization by myofilaments in living cardiac muscle

Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

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Excitation-contraction coupling and relaxation alteration in right ventricular remodelling caused by pulmonary arterial hypertension

Cited by 19 publications

References 104 publications

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure

Right Ventricle Remodeling Metabolic Signature in Experimental Pulmonary Hypertension Models of Chronic Hypoxia and Monocrotaline Exposure

The use of Ca‐transient to evaluate Ca2+ utilization by myofilaments in living cardiac muscle

Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

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The use of Ca‐transient to evaluate Ca²⁺ utilization by myofilaments in living cardiac muscle