LRRC10 is required to maintain cardiac function in response to pressure overload

We previously reported that the cardiomyocyte-specific protein, Leucine-rich repeat containing 10 (LRRC10), has critical functions in the mammalian heart. Here, we tested the role of LRRC10 in the response of the heart to biomechanical stress by performing transverse aortic constriction on Lrrc10 null (Lrrc10(-/-)) mice. Mild pressure overload induces severe cardiac dysfunction and ventricular dilation in Lrrc10(-/-) mice as compared to controls. In addition to dilation and cardiomyopathy, Lrrc10(-/-) mice showed a pronounced increase in heart weight with pressure overload stimulation and a more dramatic loss of cardiac ventricular performance, collectively suggesting that the absence of LRRC10 renders the heart more disease prone with greater hypertrophy and structural remodeling, although rates of cardiac fibrosis and myocyte drop-out were not different from control. Lrrc10(-/-) cardiomyocytes also exhibit reduced contractility in response to β-adrenergic stimulation, consistent with loss of cardiac ventricular performance after pressure overload. We have previously shown that LRRC10 interacts with actin in the heart. Here, we show that histidine 150 of LRRC10 is required for interaction with actin and this interaction is reduced after pressure overload, suggesting an integral role for LRRC10 in the response of the heart to mechanical stress. Importantly, these studies demonstrate that LRRC10 is required to maintain cardiac performance in response to pressure overload and suggest that dysregulated expression or mutation of LRRC10 may greatly sensitize human patients to more severe cardiac disease in conditions such as chronic hypertension or aortic stenosis.