Harshith Dasara

Introduction. Myocardial fibrosis is the abnormal expansion of myocardium due to excessive deposition of extracellular matrix via activation of fibroblasts.¹ Despite fibrosis having a critical role of preserving structural integrity following myocardial infarction (MI), increased future susceptibility for heart failure is the result.^2,3 Every year, over 700,000 Americans will either experience MI or die from coronary heart disease, both of which contribute to myocardial fibrosis.⁴ Recent animal studies have shown that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive calcium ion channel, is an important modulator of myofibroblast function, suggesting TRPV4 as a potential target for minimizing excess fibrotic activity and reducing the chances of heart failure.^3,5 Multiple studies elucidate how TRPV4 is mechanistically integral to fibrosis by responding to both mechanical and biochemical signals and how it is involved with transforming growth factor beta (TGF-b) and Rho/Rho kinase pathways.^6,7,8 While clinical studies are underway testing the safety of TRPV4 channel blockers in various conditions, there are none yet specifically exploring the effect of TRPV4 on myocardial fibrosis.^9,10 Methods. The effect of TRPV4 gene knockout was tested by inducing MI in mice and measuring fibrosis and cardiac function 8 weeks later.⁶ Cardiac function was measured with echocardiography, while fibrosis was assessed from heart paraffin sections.⁶ Rho kinase and promoter activity assays were used to reveal TRPV4’s relationship with the Rho/Rho kinase pathway.⁶ TRPV4’s relationship to TGF-b was revealed by introducing a TRPV4 specific antagonist and later comparing TGF-b levels to control mice.⁷ TRPV4’s ability to integrate both mechanical and biochemical signals was tested by utilizing a bleomycin-induced murine skin fibrosis model alongside immunofluorescence staining, while TGF-b levels and matrix stiffness were measured.⁸ Results. TRPV4 knockout mice displayed reduced cardiac fibrosis and preserved cardiac function following induced MI.⁶ TRPV4 also amplified the Rho/Rho kinase pathway in the wildtype mice, promoting fibroblast differentiation, while knockout mice did not.⁶ A TRPV4 antagonist inhibited proliferation of fibroblasts and revealed lower levels of TGFb1.⁷ TRPV4 deletion lead to induced activation of AKT instead of Smad3, an important signal transduction protein part of the TGFb1 pathway.⁸ Conclusions. Animal studies have consistently shown how reduced expression or blocking of TRPV4 channels can limit myocardial fibrosis. While not for myocardial fibrosis specifically, one clinical trial tested a TRPV4 channel blocker, showing no adverse events, even in heart failure patients.¹¹ All of these findings point to TRPV4 channel blockers being a viable therapeutic target for reducing myocardial fibrosis.

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