Genetic knockout of prestin limits cardiac hypertrophy in a murine pressure overload model.

Abstract

Up until recently, Prestin (Slc26a5) was considered to be exclusively expressed in the outer hair cells of the inner ear, where it serves as a voltage-to-force convertor and mediates electromotility. Our recent studies demonstrate that prestin is expressed in the heart, where it amplifies cardiac motor function. Due to prestin's ability to modulate cardiac contractility, we hypothesize that it plays a pivotal role in pathological cardiac hypertrophy. We subjected wild-type (WT) and Slc26a5-/- mice to sham operation or chronic pressure overload induced by transverse aortic constriction (TAC) surgery. Cardiac structure and function were assessed by echocardiography. We performed single cell Ca2+ transients and cell shortening recordings on isolated cardiomyocytes. Atomic force microscopy, a high-resolution technique, was also used to quantify the Young's modulus. After 8 weeks of TAC, the expression of prestin was markedly elevated in WT TAC mice relative to WT sham mice. To test whether the increased expression is maladaptive or cardioprotective, Slc26a5-/- mice underwent the same surgeries. Slc26a5-/- sham mice had depressed cardiac function relative to WT sham mice. In contrast and unexpectedly, 4 weeks after TAC, Slc26a5-/- mice exhibited blunted cardiac structural remodeling and more robust cardiac function as compared to WT TAC mice. Moreover, we found that cardiomyocytes from Slc26a5-/- mice showed more normalized Ca2+ transients and cellular shortening relative to cardiomyocytes from WT TAC mice. Our findings demonstrate that knockout of Slc26a5 is cardioprotective in a murine model of pressure overload, highlighting its crucial role in both physiological and pathological conditions. Overexpression of prestin in cardiac hypertrophy may significantly alter the mechanical properties of cardiomyocytes, leading to worsening in hypertrophy-induced cardiac dysfunction. Our study suggests that targeting prestin may represent a viable therapeutic avenue for cardiac hypertrophy.