Abstract 14045: Loss of Cardiac-Specific Gene Leucine-Rich Repeat Containing 10 (Lrrc10) Results in Dilated Cardiomyopathy, Reduced L-type Ca2+ Currents and Myocyte Contractility
Leucine-rich repeat containing 10 (LRRC10) is a cardiac-specific protein expressed in embryonic and adult hearts and plays critical roles in cardiac function. Recently, we have demonstrated that LRRC10 localizes to dyadic regions in cardiomyocytes interacts with α-actinin and α-actin. Lrrc10-null (Lrrc10-/-) mice exhibit prenatal systolic dysfunction resulting in early onset dilated cardiomyopathy and progressive postnatal cardiac dysfunction. Furthermore, hearts from Lrrc10-/- mice show altered expression for hypertrophic signaling pathway proteins. However, a mechanistic role for LRRC10 in the regulation of cardiac pathophysiology is unknown. We hypothesize that LRRC10 regulates cardiac function by facilitating myocyte contractility. The role of LRRC10 in cardiac excitation contraction coupling was investigated using the Lrrc10-/- mice. Myocyte contractility and calcium transients were studied using the video-edge detection system and fura 2-AM loading at basal levels and following perfusion with Isoproterenol (ISO, 10 nM) at 0.5 - 2 Hz pacing. Cell shortening was significantly reduced following perfusion with ISO in Lrrc10-/- myocytes (55% and 49% at 1 and 2 Hz respectively) compared to WT myocytes. Time to peak contraction and time of 50% relaxation were not altered between the Lrrc10-/- and WT myocytes at basal conditions or with ISO perfusion. Calcium transient analysis showed that there were no significant differences in peak amplitudes of [Ca2+]i between Lrrc10-/- and WT myocytes at baseline or with ISO treatment. Importantly, whole-cell voltage clamp experiments performed in ventricular myocytes from Lrrc10-/- mice demonstrated a significant reduction in the L-type Ca2+ current (ICa,L) density -2.5 0.2 pA/pF compared to -6 0.6 pA/pF in WT myocytes. Furthermore, the inactivation of the ICa,L in Lrrc10-/- myocytes was also significantly delayed. Co-immunoprecipitation and Western blot analysis from ventricular homogenates using antibodies to LRRC10 and Cav1.2 subunit of the cardiac L-type Ca2+ channels demonstrated that the two proteins were associated with one another. We conclude that LRRC10 is a novel regulator of ICa,L and Lrrc10 expression is essential for regulation of myocyte contractility and cardiac function.
- © 2013 by American Heart Association, Inc.