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

Introduction: Endoglin is an accessory receptor for the cytokine transforming growth factor beta. Reduced endoglin activity limits cardiac fibrosis due to left ventricular (LV) pressure overload. Recently, we reported that reducing endoglin activity also limits upregulation of the profibrogenic transient receptor potential canonical channel 6 (TRPC6) in the right ventricle (RV) during pressure overload. Few studies have compared TRPC channel expression in the RV versus LV. Hypothesis: We hypothesized that endoglin regulates TRPC upregulation in response to RV and LV pressure overload. Methods: To explore a functional role for endoglin as a regulator of TRPC expression in response to RV or LV pressure overload, endoglin haploinsufficient (Eng+/-) and wild-type (Eng+/+) mice were exposed to thoracic aortic (TAC) or pulmonary arterial (PAC) constriction for 10 weeks. Biventricular tissue was then analyzed by real-time polymerase chain reaction. Results: After TAC, LV levels of TPRC1 and 6 were increased in both Eng +/+ and Eng +/- mice compared to sham controls. LV levels of TRPC4 were increased in Eng +/+, not Eng +/- mice after TAC. After PAC, RV levels of TRPC1, 3, 4, and 6 were increased in Eng +/+ compared to sham controls. In contrast, chronic RV pressure overload did not increase RV levels of TRPC1, 3, 4, and 6 in Eng +/- mice compared to sham controls. Conclusions: Pressure overload induces distinct profiles of TRPC expression in the RV and LV and these effects in the RV require full endoglin activity. Taken together, these data support that endoglin may be an important and novel target of therapy to modulate RV responses to injury.

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Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.760035 ◽

2021 ◽

Vol 9 ◽

Author(s):

Tian Jia ◽

Xiaozhi Wang ◽

Yiqun Tang ◽

Wenying Yu ◽

Chenhui Li ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Transient Receptor Potential ◽

Transforming Growth Factor ◽

Receptor Potential ◽

Transforming Growth Factor Β ◽

Permeable Channel ◽

Transient Receptor ◽

Tgf Β1

Heart failure caused by cardiac fibrosis has become a major challenge of public health worldwide. Cardiomyocyte programmed cell death (PCD) and activation of fibroblasts are crucial pathological features, both of which are associated with aberrant Ca2+ influx. Transient receptor potential cation channel subfamily M member 7 (TRPM7), the major Ca2+ permeable channel, plays a regulatory role in cardiac fibrosis. In this study, we sought to explore the mechanistic details for sacubitril, a component of sacubitril/valsartan, in treating cardiac fibrosis. We demonstrated that sacubitril/valsartan could effectively ameliorate cardiac dysfunction and reduce cardiac fibrosis induced by isoprotereno (ISO) in vivo. We further investigated the anti-fibrotic effect of sacubitril in fibroblasts. LBQ657, the metabolite of sacubitril, could significantly attenuate transforming growth factor-β 1 (TGF-β1) induced cardiac fibrosis by blocking TRPM7 channel, rather than suppressing its protein expression. In addition, LBQ657 reduced hypoxia-induced cardiomyocyte PCD via suppression of Ca2+ influx regulated by TRPM7. These findings suggested that sacubitril ameliorated cardiac fibrosis by acting on both fibroblasts and cardiomyocytes through inhibiting TRPM7 channel.

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Role of Known Transient Receptor Potential Vanilloid Channels in Modulating Cardiac Mechanobiology

Frontiers in Physiology ◽

10.3389/fphys.2021.734113 ◽

2021 ◽

Vol 12 ◽

Author(s):

Michael Miller ◽

Sheryl E. Koch ◽

Adam Veteto ◽

Timothy Domeier ◽

Jack Rubinstein

Keyword(s):

Transient Receptor Potential ◽

Trp Channels ◽

Pressure Overload ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Functional Responses ◽

Functional Protein ◽

Trpv Channels ◽

Transient Receptor ◽

And Function

The transient receptor potential (TRP) channels have been described in almost every mammalian cell type. Several members of the Vanilloid (TRPV) subtype have been found to play important roles in modulating cardiac structure and function through Ca2+ handling in response to systemic and local mechanobiological cues. In this review, we will consider the most studied TRPV channels in the cardiovascular field; transient receptor potential vanilloid 1 as a modulator of cardiac hypertrophy; transient receptor potential vanilloid 2 as a structural and functional protein; transient receptor potential vanilloid 3 in the development of hypertrophy and myocardial fibrosis; and transient receptor potential vanilloid 4 in its roles modulating the fibrotic and functional responses of the heart to pressure overload. Lastly, we will also review the potential overlapping roles of these channels with other TRP proteins as well as the advances in translational and clinical arenas associated with TRPV channels.

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