Abstract 15465: Calpain Inhibition by Constitutive Calpastatin Overexpression Leads to Increased Mortality and More Severe Left Ventricular Dysfunction at Long Term After Myocardial Infarction in Mice
Introduction: Calpains play an essential role in left ventricular (LV) remodeling post myocardial infarction (MI). Its inhibition reduces LV dysfunction at short term post MI. We examined if calpain inhibition by calpastatin (cast) overexpression is beneficial long-term post MI.
Material and methods: Thirty-seven wild-type (WT) C57BL/6 and 42 transgenic (TG) mice overexpressing cast underwent left anterior descending (LAD) coronary artery ligation; 16 TG and 18 WT shams served as controls. Mice were sacrificed at 6w post MI. MI size was quantified by echocardiography and scar planimetry. In remote myocardium (RM) fibrosis and hypertrophy were quantified histologically; calpain1+2, cast, SERCA2a, PLB expression by Western blot; calpain activity by fluorometry.
Results: Acute post MI mortality (<72h) was similar. Mortality from 3d to 6w post MI was increased in TG (18/41 vs. 7/35 in WT; log-rank p=0.036; HR 2.44 [1.02-5.85]), driven by LV rupture. MI size and LV dimensions were similar in TG vs. WT. LV contractility was reduced in TG-MI (+dP/dt 7635±732mmHg, N=7, vs. 9084±1413mmHg in WT-MI, N=6, P=0.039). Lung weight was increased in TG-MI (190±59mg vs. 139±18mg in TG-sham, P=0.004). Pulmonary congestion in WT-MI was not significant. RM of TG- vs. WT-MI mice showed more fibrosis (13±0.27 vs 7.9±1.24%; P=0.017), more myocyte hypertrophy (541±22 vs. 442±16µm²; P=0.02), 85% increase in calpain 1 expression (P=0.019), similar calpain 2 levels, 60% increase in calpain activity (P=0.046), 25% decrease in SERCA2a expression (P=0.03) and 44% decrease of the SERCA2a/PLB ratio (P=0.006). The baseline difference in myocardial cast expression (+56% TG- vs. WT-sham, P=0.04) was blunted 6w post MI due to a 43% increase in cast expression in WT-MI mice (P=0.036 vs. WT-sham).
Conlusion: Calpain inhibition by cast overexpression is deleterious post MI. It increases mortality and leads to more severe LV dysfunction at long term post MI, related to more important interstitial and cardiac myocyte adverse remodelling.
- © 2011 by American Heart Association, Inc.