LRRC 10 is required to maintain cardiac function in response to pressure overload 1 2

24 We previously reported that the cardiomyocyte-specific protein, Leucine-rich 25 repeat containing 10 (LRRC10), has critical functions in the mammalian heart. Here, we 26 tested the role of LRRC10 in the response of the heart to biomechanical stress by 27 performing transverse aortic constriction on Lrrc10 null (Lrrc10) mice. Mild pressure 28 overload induces severe cardiac dysfunction and ventricular dilation in Lrrc10 mice as 29 compared to controls. In addition to dilation and cardiomyopathy, Lrrc10 mice showed 30 a pronounced increase in heart weight with pressure overload stimulation and a more 31 dramatic loss of cardiac ventricular performance, collectively suggesting that the absence 32 of LRRC10 renders the heart more disease prone with greater hypertrophy and structural 33 remodeling, although rates of cardiac fibrosis and myocyte drop-out were not different 34 from control. Lrrc10 cardiomyocytes also exhibit reduced contractility in response to β35 adrenergic stimulation, consistent with loss of cardiac ventricular performance after 36 pressure overload. We have previously shown that LRRC10 interacts with actin in the 37 heart. Here, we show that histidine 150 of LRRC10 is required for interaction with actin 38 and this interaction is reduced after pressure overload, suggesting an integral role for 39 LRRC10 in the response of the heart to mechanical stress. Importantly, these studies 40 demonstrate that LRRC10 is required to maintain cardiac performance in response to 41 pressure overload and suggest that dysregulated expression or mutation of LRRC10 may 42 greatly sensitize human patients to more severe cardiac disease in conditions such as 43 chronic hypertension or aortic stenosis. 44 45