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(Hypertension. 2007;49:865.)
© 2007 American Heart Association, Inc.

Original Articles

ß1 Integrins Modulate ß-Adrenergic Receptor–Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling

Prasanna Krishnamurthy; Venkateswaran Subramanian; Mahipal Singh; Krishna Singh

From the Department of Physiology, James H. Quillen College of Medicine, James H. Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City.

Correspondence to Krishna Singh, Department of Physiology, James H. Quillen College of Medicine, East Tennessee State University, PO Box 70576, Johnson City, TN 37614. E-mail singhk{at}etsu.edu

Sympathetic nerve activity increases in the heart during cardiac failure. Here, we hypothesized that ß1 integrins play a protective role in chronic ß-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 ß1 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 ß1 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, ß1 integrins play a crucial role in ß-adrenergic receptor–stimulated myocardial remodeling with effects on cardiac myocyte hypertrophy, apoptosis, and left ventricular function.

Key Words: ß1 integrins • ß-adrenergic receptor • apoptosis • heart failure • MMPs • JNK

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Ionotropic Stress and Integrin: Another Link to Myocardial Remodeling

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