[F31] The Role of TRPV4 in Right Ventricular Cardiomyocyte Ca2+ Dysregulation in Pulmonary Hypertension

Ente: National Heart Lung and Blood Institute

Scadenza: 2028-07-31

Importo max: $36,017

Paese: US

Descrizione

Project Summary and Abstract: The incidence and prevalence of chronic respiratory diseases and pulmonary hypertension (PH) is rising worldwide. PH leads to right ventricular (RV) pressure overload and progressive dysfunction with associated arrhythmias. Approximately 1% of the global population suffers from at least one subtype of PH, making the resulting cardiac dysfunction and arrhythmias a significant public health concern. The right ventricle has historically been understudied compared to the left, contributing to the current lack of RV-targeted therapies available to PH patients. Heart failure, including RV failure, is associated with disrupted cardiomyocyte excitation- contraction coupling and arrhythmias due to aberrant Ca²⁺ homeostasis. The Transient Receptor Potential Vanilloid 4 (TRPV4) cation channel is upregulated in left ventricular pressure overload and failure in mouse and human hearts, but its functional role in RV myocytes in PH is unknown. Increased TRPV4 activity contributes to cardiac hypercontractility and arrhythmogenesis in the left ventricle through elevated Ca²⁺ influx. TRPV4 is also activated by Angiotensin II (AngII) Type 1 Receptor signaling in various cell types, but this axis has yet to be characterized in cardiomyocytes. Notably, AngII levels are elevated in animal models and patients with PH. Thus, the purpose of this proposal is to train the applicant in both cellular and organ-level physiology to study the AngII- TRPV4 signaling axis in RV cardiomyocytes of mice treated with intratracheal bleomycin (PH) or saline (Sham). Specific Aim 1 will use a novel genetic model expressing a functional TRPV4-EGFP fusion protein. Cardiomyocytes from PH and Sham mice will be isolated and imaged to assess TRPV4-EGFP expression and membrane localization. This aim will also employ whole-cell patch clamp electrophysiology to examine AngII- induced TRPV4 currents in ventricular myocytes with pharmacologic inhibition or genetic deletion of TRPV4. Specific Aim 2 will use calcium dyes or mice with cardiomyocyte-specific GCaMP6f expression, combined with advanced microscopy and pharmacologic TRPV4 inhibition or genetic TRPV4 deletion, to study acute AngII treatment of RV cardiomyocytes in Sham and PH mice. Specific Aim 3 will assess in vivo cardiac function using echocardiography in Sham and PH mice with chronic pharmacologic TRPV4 inhibition or cardiomyocyte-specific TRPV4 deletion. Mice will be challenged with intravenous AngII to examine the impact of TRPV4 inhibition on contractility and arrhythmogenesis. Findings in mouse myocytes will be correlated with human samples. Completion of this proposal will provide the applicant with the necessary tools to investigate cardiomyocyte Ca²⁺ dynamics as a therapeutic target in PH and cardiac arrhythmias more broadly as a physician-scientist. Istituzione: UNIVERSITY OF MISSOURI-COLUMBIA PI: Andrew Behrmann Progetto: 1F31HL186708-01

Settori: National Heart Lung and Blood Institute

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