Abstract 801: Differential Regulation Of Ca/calmodulin-dependent Protein Kinase II (CaMKII) In Cardiac Hypertrophy In The Mouse: Pressure Overload Versus Volume Overload
Transgenic overexpression of CaMKIIδc (cytosolic isoform) leads to hypertrophy, impaired Ca homeostasis, heart failure, and contributes to arrhythmias. The role of CaMKII in hypertrophy caused by biomechanical load is unclear. We investigated pressure overload (PO) induced by transverse aortic constriction (TAC) and volume overload (VO) induced by aortocaval shunt (SHUNT) for mouse hearts. TAC mice (7 d post surgery) showed left ventricular (LV) hypertrophy (LV/body weight) with 5.5±0.3 vs. sham with 3.8±0.1 mg/g (n=6 each, P<0.01) but unaltered right ventricular (RV)/body weight. SHUNT mice showed both LV (4.7±0.4 vs. 3.6±0.2 mg/g) and RV (1.4±0.1 vs. 1.0±0.1 mg/g, n=5 vs. 6, P<0.05) hypertrophy vs. sham. Echocardiography revealed an increased interventricular septum thickness (IVS) in TAC compared to sham indicating concentric hypertrophy (1.2±0.1 vs. 0.8±0.1 mm, n=6 vs. 6, P<0.01). SHUNT mice did not show changes in IVS, but increased LV internal diameter (LVID) both at diastole (3.77±0.1 vs. 2.9±0.1 mm, n=6 vs. 3, P<0.01) and systole compared to sham indicating eccentric hypertrophy. Western blot analyses of TAC mice had 35% higher CaMKII expression (CaMKIIδc as well as nuclear isoform CaMKIIδb, n=5 vs. 4, P<0.05) and a 2-fold increased CaMKII activity (P-CaMKII; n=3 each, P<0.05) in LV of TAC mice vs. sham. In contrast there was no upregulation or activation of any CaMKII isoform in LV or RV in SHUNT mice. Similar results were found for both models after 29 and 45 d post surgery. Functional measurements in isolated myocytes from TAC (7 d) mice showed higher Ca transients (F/F0) vs. sham at all stimulation frequencies (1–8 Hz; 1 Hz: 2.5±0.1 vs. 2.2±0.1, P<0.05) and increased contractility (1 Hz: 4.9±0.3 vs. 3.9±0.4 %, n=44 vs. 38, P<0.05). SR Ca content was not altered between TAC and sham (F/F0: 3.5±0.2 vs. 3.6±0.3, n=28 vs. 18) but fractional SR Ca release was increased and inhibition of CaMKII (KN-93, 1 μmol/L) increased SR Ca content. We conclude from these data that CaMKII is differentially regulated in PO vs. VO hypertrophy. In our experiments PO evoked concentric hypertrophy and elevation and activation of CaMKII leading to increased fractional SR Ca release whereas in eccentric hypertrophy induced by VO there was no alteration of CaMKII levels or activation.