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(Circulation Research. 2006;99:1403.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Integrin Activation in the Heart

A Link Between Electrical and Contractile Dysfunction?

Maria L. Valencik, Dongfang Zhang, Bonnie Punske, Ping Hu, John A. McDonald, Sheldon E. Litwin

From the Department of Biochemistry (M.L.V., J.A.M.), University of Nevada School of Medicine, Reno; Cardiology Division (D.Z., P.H., S.E.L.), University of Utah Hospitals and Clinics, Salt Lake City; Veterans Affairs Medical Center (S.E.L.), Salt Lake City; and Nora Eccles Harrison Cardiovascular Research and Training Institute (B.P.), University of Utah, Salt Lake City.

Correspondence to Maria L. Valencik, UNR Biochemistry M/S 330, Reno, NV 89557. E-mail mvalen{at}unr.edu; or S.E. Litwin, Cardiology, 4A100SOM, 30 N. 1900 E., Salt Lake City, UT 84132. E-mail sheldon.litwin@hsc.utah.edu

Integrins mechanically link the cytoskeleton to the extracellular matrix in cardiac myocytes and are thereby involved in mechanotransduction. Integrins appear to be necessary for cardiac myocyte hypertrophy. To determine the effect of increased integrin ligation and signaling on adult cardiac function, a heart-specific truncated ₅ integrin (gain of function) was conditionally expressed in mice. Four days later, we observed an 80% reduction in amplitude of the QRS complex, profound systolic dysfunction, decreased connexin43, loss of gap junctions, and abnormal intercalated discs. Surprisingly, isolated left ventricular myocytes contracted normally and exhibited normal Ca²⁺ transients. This suggested that cell/cell electrical and/or mechanical coupling was disrupted. To distinguish electrical from mechanical coupling deficits, we compared the papillary muscle force generated by electrically stimulated versus rapid cooling contractions in which intracellular Ca²⁺ is released without electrical depolarization. Both were decreased in the transgenic muscle. However, electrically stimulated contractions were more significantly reduced than rapid cooling contractures. This suggests a component of cell/cell electrical uncoupling. Optical mapping revealed a loss of the normal elliptical isochronal activation pattern implying a loss of preferential conduction through gap junctions. For the first time, we have shown that integrins can regulate both mechanical and electrical coupling in the adult heart, even in the absence of primary hemodynamic alterations. Furthermore, we demonstrated that unregulated integrin activation leads to both contractile dysfunction and arrhythmias.

Key Words: integrin • heart failure • extracellular matrix • cardiomyopathy

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