Abstract 340: Ablation of the Plasma Membrane Calcium ATPase 4 (PMCA4) Attenuates the Pressure Overload-Induced Hypertrophic Response and Protects against the Development of Left Ventricular Dysfunction
We have previously reported that isoform 4 of the plasma membrane calcium/calmodulin-dependent ATPase (PMCA4) interacts with and modulates neuronal nitric oxide synthase (nNOS) activity. Using transgenic mice overexpressing PMCA4 in the heart, we have demonstrated that the PMCA4-nNOS complex modulates cardiac contractility without altering global intracellular calcium transients ( Circulation 2007;115:483– 492). Here, we used PMCA4 knock out (PMCA4−/−) mice to test whether this novel signaling axis is involved in the regulation of mechanical stress-induced cardiac hypertrophy. PMCA4−/− mice and wild type (WT) littermates were subjected to transverse aortic constriction (TAC) or sham operation. Five weeks after TAC, PMCA4−/− mice showed a markedly reduced hypertrophic response compared to WT as indicated by left ventricular (LV) mass/tibia length ratio (table 1⇓). Histological analysis demonstrated a significantly reduced cardiomyocytes cross sectional area in PMCA4−/− TAC compared to WT-TAC. The activation of the fetal gene program (ANP, BNP, and βMHC) was also blunted in PMCA4−/− TAC mice. Invasive hemodynamic and echocardiographic assessments revealed that WT-TAC animals displayed reduced contractility as well as enlargement of LV chamber dimension compared to PMCA4−/− TAC mice as indicated by preload recruitable stroke work (PRSW) and LV end diastolic dimension (LVEDD) suggesting a protection from the development of LV dysfunction in PMCA4−/− mice. We then analysed the molecular pathway which might be modified by PMCA4 gene ablation. While ERK1/2, JNK and GSK3β were not differently activated, we found that Akt activation was reduced in PMCA4−/− TAC compared to WT-TAC, possibly via an NO dependent mechanism. Our results suggest that PMCA4 is a powerful regulator of myocardial hypertrophy and further strengthens the notion that PMCA4 is part of a novel signaling pathway in the myocardium.