Abstract 13416: Phospholipase cβ1b Depletes Sarcoplasmic Reticulum Calcium Content and Causes Cardiac Contractile Dysfunction
Phospholipase Cβ1b (PLCβ1b) is the immediate effector of Gq and Gq-coupled receptors (α1-adrenergic-, endothelin- and angiotensin II- receptors). Dilated atria from humans, mice and sheep show heightened expression and activity of PLCβ1b, and PLCβ1b activity correlates with left atrial size. We hypothesised that heightened PLCβ1b contributes to disease progression. To increase PLCβ1b expression to levels observed in dilated atria, we administered adeno-associated viral vectors carrying a FLAG-PLCβ1b construct (rAAV6-FLAG-PLCβ1b). FLAG-PLCβ1b expression was measured by western blot and by immunofluorescence and sarcoplasmic reticulum (SR) calcium content was measured using confocal imaging. FLAG-PLCβ1b was expressed in all of the chambers of the heart, but was highest in left ventricle and lowest in left atrium. In ventricular myocytes, FLAG-PLCβ1b expression was observed in >90% of the cells and was localized to the sarcolemma and T-tubules. PLCβ1b-expression caused a lowering of SR calcium content. Cardiac function was assessed by echocardiography and by invasive hemodynamic measurements. PLCβ1b expression caused a rapid loss of contractility, which was observed within 4 weeks of vector administration (Fractional shortening 43 ± 1.7 to 32 ± 1.4 %, mean ± sem, n=15, p<0.01), and was followed by left atrial dilatation (6.4±0.16 to 8.2±0.52 mm2 p<0.01) and left ventricular hypertrophy (LV/BWt; 2.8±0.13 to 3.4±0.09 mg/g, p<0.01), within 12 weeks and 20 weeks, respectively. PLCβ1b suppressed contractile responses to β-adrenergic receptor activation (dP/dtMAX 17630 ± 760 to 15500 ± 520 mmHg/sec, p<0.001). We conclude that heightened PLCβ1b activity in dilated human atria contributes to disease progression by depleting SR calcium stores and thereby lowering contractile activity. In addition, chronically heightened PLCβ1b promotes hypertrophy and dilatation. PLCβ1b is a cardiac-specific signaling system, and thus provides an ideal therapeutic target.
- © 2013 by American Heart Association, Inc.