Abstract 19382: Ablation of the Cardiac-Specific Gene Leucine-Rich Containing 10 (lrrc10) Results in Dilated Cariomyopathy

Abstract

Dilated cardiomyopathy is the most common form of cardiomyopathy and is a leading cause of heart failure. Leucine-rich repeat containing 10 (LRRC10) is a cardiac-specific protein containing leucine-rich repeat motifs ideal for protein:protein interactions. We have previously shown that LRRC10 is essential for proper cardiac function in developing zebrafish. However, the role of LRRC10 in mammalian cardiac physiology remains unknown. To determine if LRRC10 is critical for mammalian cardiac function, Lrrc10-null (Lrrc10-/-) mice were evaluated by echocardiography. Lrrc10-/- mice exhibit prenatal systolic dysfunction and progressive dilated cardiomyopathy in postnatal life. Importantly, Lrrc10-/- mice have diminished cardiac performance in utero, prior to ventricular dilation observed in young adults. Gene expression profiling revealed that cardiac muscle contraction and oxidative phosphorylation are the most upregulated pathways in adult Lrrc10-/- hearts. We demonstrate that LRRC10 physically interacts with α-actinin and actin isoforms by coimmunoprecipitation, GST pulldown, and yeast two-hybrid screening, suggesting that LRRC10 may provide a link between the myofilament Z-disc and the actin cytoskeleton. Interaction of LRRC10 with α-actinin and actin positions it in ideal location in the cardiomyocyte to sense or transduce signals in response to biomechanical stress. To test the role of LRRC10 in response to biomechanical stress, transverse aortic constriction (TAC) was performed. Lrrc10-/- mice exhibit exacerbated and accelerated cardiomyopathy in response to 28 days of TAC with markedly greater left ventricular (LV) chamber dilation and severely compromised systolic and diastolic function relative to controls. Moreover, endogenous Lrrc10 expression is downregulated in controls in response to TAC, suggesting an important role for LRRC10 in cardiac adaptation to biomechanical stress. In summary, we identify the cardiac-specific factor Lrrc10 as a novel dilated cardiomyopathy candidate gene. LRRC10 is essential for normal cardiac function and is indispensible for proper adaptation of the mammalian heart to biomechanical stress.