TRPV2 is critical for the maintenance of cardiac structure and function in mice

Abstract

The heart has a dynamic compensatory mechanism for haemodynamic stress. However, the molecular details of how mechanical forces are transduced in the heart are unclear. Here we show that the transient receptor potential, vanilloid family type 2 (TRPV2) cation channel is critical for the maintenance of cardiac structure and function. Within 4 days of eliminating TRPV2 from hearts of the adult mice, cardiac function declines severely, with disorganization of the intercalated discs that support mechanical coupling with neighbouring myocytes and myocardial conduction defects. After 9 days, cell shortening and Ca2+ handling by single myocytes are impaired in TRPV2-deficient hearts. TRPV2-deficient neonatal cardiomyocytes form no intercalated discs and show no extracellular Ca2+-dependent intracellular Ca2+ increase and insulin-like growth factor (IGF-1) secretion in response to stretch stimulation. We further demonstrate that IGF-1 receptor/PI3K/Akt pathway signalling is significantly downregulated in TRPV2-deficient hearts, and that IGF-1 administration partially prevents chamber dilation and impairment in cardiac pump function in these hearts. Our results improve our understanding of the molecular processes underlying the maintenance of cardiac structure and function.

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

“…This finding is consistent with our prior murine studies where probenecid administration increased the EF in healthy mice between 5% and 8% and up to 19% in mice with reduced systolic function at baseline secondary to an induced ischemic event 18. Furthermore, this finding is also consistent with other previous reports that demonstrate that TRPV2 is a stretch‐mediated channel31, 32, 33; thus patients with markedly impaired systolic function and/or significantly dilated left ventricles may be particularly sensitive to its inotropic effects. Specifically, we found that probenecid increased contractility in most patients after a single week of therapy and that the change was more pronounced in patients with lower baseline function, though of course the clinical relevance of this change will require further studies as described below.…”

Role of Thermo-Sensitive Transient Receptor Potential Channels in Brown Adipose Tissue

“…90,91) TRPV2 is also expressed in nonneuron cells, such as pancreatic β-cells 92) and cardiomyocytes. 93) TRPV2 has been reported expressed in WAT and BAT. 56) We previously showed that TRPV2 is more highly expressed in mouse brown adipocytes than TRPV1, TRPV3, TRPV4, and TRPM8.…”

Inhibitory effect of progesterone during early embryonic development: Suppression of myocardial differentiation and calcium-related transcriptome by progesterone in mESCs

“…These results indicate that influx of cytosolic Ca 2+ through TRPV2 affects the cardiac differentiation process and differentiated cardiomyocytes. In the murine model, cardiomyocytes isolated from TRPV2-knockout mice did not form intercalated discs and low cytosolic Ca 2+ levels were detected [25].…”

“…In a previous study, knockdown of TRPV2 in the hearts of adult mice resulted in severe decline of cardiac function and disorganization of the intercalated discs within 4 days. After 9 days, single myocytes from TRPV2-deficient hearts showed impaired cell shortening and Ca 2+ handling [25].…”