Supporting data for "Modelling Treatment (TRPV4 inhibitor) Response for Lamin A:C Related Dilated Cardiomyopathy in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes and Transgenic Mice"

<p dir="ltr">This project investigate the protective effect of TRPV4 inhibitor in LMNA p.R225X related DCM models. We evaluated the anti-apoptotic and anti-fibrotic effects of TRPV4 inhibitor in these models, examined cardiac function with TRPV4 inhibitor treatment, and validated the interactions between TRPV4 inhibitor and truncated lamin proteins. The in-vivo and in-vitro experiments were conducted with TRPV4 inhibitor treatment, including immunofluorescence of target proteins, western blotting, apoptosis analysis, and calcium measurement in LMNA p.R225X hiPSC-CMs, as well as protein analysis, cardiac function analysis in LMMA p.R225X mice. In vitro studies involved differentiating hiPSCs with the LMNA p.R225X variant into cardiomyocytes to evaluate how TRPV4 inhibitor influences apoptosis associated with LMNA-related DCM. Additionally, changes in lamin A/C were examined in lmnaWT/WT and lmnaR225X/WT hiPSC-CMs subjected to stresses. TRPV4 inhibitor treatment was found to reduce nuclear blebbing caused by chemical stress, as well as decrease apoptosis and the senescence-associated secretory phenotype at both protein and mRNA levels under mechanical stress. In vivo, the therapeutic potential of RN was assessed in transgenic mice carrying the LMNA p.R225X mutation. These mice received weekly intravenous injections of RN over four months, with cardiac function monitored monthly via echocardiography. The results demonstrated that RN improved systolic function and reduced cardiac fibrosis in lmnaR225X/WT mice.</p>