Towards Sabotaging the Link Between Hypertension and Cardiac Hypertrophy
The heart becomes larger and weaker in response to the raised blood pressure of hypertension, though inflammatory signaling clearly also plays an important role. Note the study that showed clearance of senescent cells, and thus removal of their pro-inflammatory signaling, reversed cardiac hypertrophy in mice. In the research noted here, scientists discuss the sensing mechanisms that link blood pressure with hypertrophy of the heart. Sabotaging that system is not as good as prevention of hypertension, as targeting deeper issues should always be better than preventing just a few of their consequences, but will no doubt give rise to the development of small molecule drugs regardless.
Despite advances in cardiovascular medicine over the last 30 years, pathological left ventricular (LV) hypertrophy (LVH) secondary to pressure overload resulting from hypertension or aortic stenosis remains a powerful independent predictor of cardiovascular mortality and morbidity. Thus far, the only treatment available for this condition is blood pressure reduction with anti-hypertensive medications or replacement of a stenotic aortic valve. These strategies do not fully reverse the pathological remodeling that occurs once LVH is established.
We have shown recently that the Ca2+-activated TRPM4 ion channel acts as a positive regulator of pressure overload-induced cardiac hypertrophy. Given that TRPM4 is not activated by membrane stretch, the question remains as to the identity of the molecule at the start of the hypertrophic signaling cascade that senses changes in mechanical load within the myocardium and transduces that mechanical signal into a chemical signal that activates TRPM4. A prime candidate to act upstream of TRPM4 within this mechanosensory signaling cascade that drives LVH is the Ca2+-permeable mechanosensitive ion channel, Piezo1. Despite the significant evidence for a key role of Piezo1 channels in vascular physiology and pathophysiology, little is known about the role of Piezo1 in cardiac biology.
Here we show that Piezo1, which is both stretch-activated and Ca2+-permeable, is the mechanosensor that transduces increased myocardial forces into the chemical signal that initiates hypertrophic signaling via a close physical interaction with TRPM4. Cardiomyocyte-specific deletion of Piezo1 in adult mice inhibited the hypertrophic response. Piezo1 deletion prevented upregulation of the sodium-calcium exchanger and changes in other Ca2+ handling proteins after pressure overload. These findings establish Piezo1 as the cardiomyocyte mechanosensor that instigates the maladaptive hypertrophic response to pressure overload, and as a potential therapeutic target.