Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats

Abstract

Previous studies have established integrins as cell surface receptors that mediate cardiomyocyte-extracellular matrix (ECM) attachments. This study sought to determine the contributions of the myocardial β1- and β3-integrin subunits to ventricular dilatation and coronary flow regulation using a blood-perfused isolated heart preparation. Furthermore, cardiomyocyte adhesion to collagen types I and IV, fibronectin, and laminin with and without a β1-integrin subunit neutralizing antibody was assessed during the course of remodeling secondary to a sustained cardiac volume overload, including the onset of heart failure. Isolated cardiomyocytes were obtained during the initial, compensated, and decompensated phases of remodeling resulting from an aortocaval fistula created in 8-wk-old male Sprague-Dawley rats. Blocking the β1-integrin subunit in isolated normal hearts produced ventricular dilatation, whereas this was not the case when the β3-subunit was blocked. Substantial reductions in cardiomyocyte adhesion coincided with the previously documented development of ventricular dilatation and decreased contractility postfistula, with the β1-integrin contribution to adhesion ranging from 28% to 73% over the course of remodeling being essentially substrate independent. In contrast, both integrin subunits were found to be involved in regulating coronary vascular resistance. It is concluded that marked reductions in integrin-mediated cardiomyocyte adhesion to the ECM play a significant role in the progression of adverse myocardial remodeling that leads to heart failure. Furthermore, although both the β1- and β3-integrin subunits were involved in regulating coronary vascular resistance, only inhibition of β1-integrin-mediated adhesion resulted in ventricular dilatation of the normal heart.

Differential Effects of Prevention and Reversal Treatment with Lisinopril on Left Ventricular Remodelling in a Rat Model of Heart Failure

“…Another contributing factor may be that lisinopril has effects on integrin function. We recently showed that infusion of a neutralising antibody against β1-integrin, but not β3-integrin, into isolated hearts caused an increase in V 0 without inducing a change in compliance [15]. Thus, a loss of β1-integrin function appears to play a causative role in producing LV dilatation, but not LV compliance.…”

Cellular Mechanotransduction: From Tension to Function

“…Due to its involvement in the stretching activity of the cardiomyocytes in vivo ( Yutao et al, 2006 ), in beta-adrenergic stimulation, and in hypertrophic response after hemodynamic load ( Li et al, 2012 ), integrin-β1 inhibition results in heart dilation ( Stewart et al, 2014 ).…”

Epigenetic modulation of tenascin C in the heart

“…In our previous study TN-C-KO mice showed preserved left ventricular function which was accompanied by a significantly reduced left ventricular dilatation [3]. Dysregulation of integrin b1 has been demonstrated to play a role in CMC apoptosis [31] and left ventricular dilatation [32]. Furthermore, Hessel et al [33] found that pressure overload-induced right ventricular failure was associated with TN-C upregulation and concomitant reduction of integrin a6.…”