β1 Integrins Modulate β-Adrenergic Receptor–Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling

Abstract

Sympathetic nerve activity increases in the heart during cardiac failure. Here, we hypothesized that β1 integrins play a protective role in chronic β-adrenergic receptor–stimulated cardiac myocyte apoptosis and heart failure. l -isoproterenol (iso; 400 μg/kg per hour) was infused in a group of wild-type (WT) and β1 integrin heterozygous knockout (hKO) mice. Left ventricular structural and functional remodeling was studied at 7 and 28 days of iso-infusion. Western blot analysis demonstrated reduced β1 integrin levels in the myocardium of hKO-sham. Iso-infusion increased heart weight:body weight ratios in both groups. However, the increase was significantly higher in WT-iso. M-mode echocardiography indicated increased left ventricular end-diastolic diameter, percentage of fractional shortening, and ejection fraction in the WT-iso group. The percentage of fractional shortening and ejection fraction were significantly lower in hKO-iso versus hKO-sham and WT-iso. Peak left ventricular developed pressure and left ventricular end-diastolic pressure measured using Langendorff–perfusion analyses were significantly higher in the WT-iso group ( P <0.05 versus WT-sham and hKO-Iso). The number of TUNEL-positive myocytes was significantly higher in hKO-iso hearts 7 and 28 days after iso-infusion. The increase in myocyte cross-sectional area and fibrosis was higher in the WT-iso group. Matrix metalloproteinase-9 protein levels were significantly higher in WT-iso, whereas matrix metalloproteinase-2 levels were increased in hKO-iso hearts. Iso-infusion increased phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in both groups. The increase in c-Jun N-terminal kinase phosphorylation was significantly higher in hKO-iso ( P <0.001 versus WT-iso). Thus, β1 integrins play a crucial role in β-adrenergic receptor–stimulated myocardial remodeling with effects on cardiac myocyte hypertrophy, apoptosis, and left ventricular function.