Ionotropic stress and integrin: another link to myocardial remodeling.

Cardiac remodeling is an adaptive response to chronically increased wall stress. Adaptive remodeling of the myocardium, caused either by increased workload or ionotropic stress, requires mediators for the communication of cardiac cells with their surrounding extracellular matrix.1 Integrins are likely candidates that transduce increased mechanical force into the intracellular biochemical signals. In this issue of Hypertension, Krishnamurthy et al2 report a potential role of myocardial 1-integrin in the adaptive and maladaptive remodeling that occurs in isoproterenol-induced left ventricular hypertrophy. To place the findings of this study in context with emerging studies regarding myocardial remodeling and the progression to left ventricular failure, a brief review of the biology of 1-integrin with respect to myocardial hypertrophy and remodeling is presented here. Integrins are heterodimeric cell-surface receptors composed of and subunits that function as adhesive and signaling molecules, as well as mechanotransducers.3 In noncardiac cells, it has been demonstrated that integrins respond to abnormal strain in a manner similar to that which would be found during pressure or volume overload in the heart.4 Integrins are expressed in various types of cells, including leukocytes, endothelial cells, vascular smooth muscle cells, fibroblasts, and myocytes. Previously, integrins were considered as the structural protein essential for maintaining the integrity of the cell–matrix interaction.3 Emerging studies have established the role of integrins in signal transduction cascades involved in cell migration, proliferation, and growth. 1-Integrin is a dominant subunit expressed in the heart, which is shown to participate in the hypertrophic response of cardiac ventricular myocytes.5 The study by Krishnamurthy et al2 provides some unique insights into the potential role of integrin in left ventricular remodeling and function. This study used -adrenergic stimulus to induce cardiac stress in wild-type and 1-integrin–deficient mice and examined 1-integrin function with respect to left ventricular remodeling and failure. In integrin-deficient mice, -adrenergic receptor stimulation failed to increase myocardial fractional shortening and ejection fraction. These findings were associated with increased cardiomyocyte apoptosis. It is often speculated that progressive deterioration of left ventricular function in heart failure is because of ongoing loss of viable cardiomyocytes. Although these findings created considerable enthusiasm, some skepticism still remains as to whether cardiomyocyte apoptosis plays an important role in the progression of heart failure. The data presented by Krishnamurthy et al2 regarding the putative role of 1-integrin in left ventricular remodeling and function are provocative in several ways. First, increased levels of 1-integrin were identified in mice after -adrenergic receptor stimulation. Second, 1-integrin– deficient mice that received isoproterenol infusion for 4 weeks had higher levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. Earlier, these investigators have demonstrated that matrix metalloproteinase-2 interferes with the phosphorylation of focal adhesion kinase that mediates survival signals of 1-integrin and activates c-Jun N-terminal kinase–dependent myocyte apoptosis.6 Activation of c-Jun N-terminal kinase is suggested to play a role in the activation of the mitochondrial death pathway of apoptosis in cells of cardiac and noncardiac origin.7,8 The authors observed greater increase in c-Jun N-terminal kinase activation in 1-integrin–deficient mice after isoproterenol infusion.2 Taken together, these studies suggest that increased matrix metalloproteinase-2 expression and activity may induce cardiac myocyte apoptosis in 1-integrin–deficient mice via the involvement of the c-Jun N-terminal kinase–dependent mitochondrial pathway. In addition to their antiapoptotic effects, integrins are shown to mediate stretch-dependent matricellular response in chronic pressure overload. Integrins associate with signaling molecules in the focal adhesion complex, which act both as a signaling device and a connection to cytoskeleton.9,10 On stimulation, integrins interact with transducing molecules like P125 focal adhesion kinase, of which the amino-terminal domain binds to the intracellular domain of the 1and 3-integrins, whereas its carboxyterminal binds to the SH2 and SH3 domains of several proteins involved in focal adhesion assembly and signal transduction. Ionotropic stress or mechanical stretch leads to the activation of the integrin-linked focal adhesion complex and phosphorylation of focal adhesion kinase at various tyrosine residues.9,10 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Hypertension and Vascular Research Division (S.P.), Henry Ford Health System, Detroit, Mich; and the Department of Internal Medicine (U.C.S.), Rosalind Franklin University Medical School, North Chicago, Ill. Correspondence to Umesh C. Sharma, Department of Internal Medicine, Rosalind Franklin University Medical School, 3333 Green Bay Rd, North Chicago, IL. E-mail [email protected] (Hypertension. 2007;49:1-2.) © 2007 American Heart Association, Inc.