Integrins Are the Necessary Links to Hypertrophic Growth in Cardiomyocytes

Abstract

To compensate for hemodynamic overload of the heart, an event which stretches the myocardium, growth and survival signaling are activated in cardiac muscle cells (cardiomyocytes). Integrins serve as the signaling receptors of cardiomyocytes responsible for mechanotransduction toward intracellular signaling. The main integrin heterodimers on the cardiomyocyte surface are α 5 β 1 and α v β 3, and elimination of either β 1 or β 3 integrins impedes pressure-induced hypertrophic signaling and leads to increased mortality. The growth signaling pathways downstream of β 1 and β 3 integrins are well characterized. However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β 1 and β 3 integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt. Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

“…As fibrillin-1 microfibrils interact with integrin receptors, microfibrillar alterations might disturb mechanosignaling through the integrin pathway leading to reduced cardiomyocyte contractility (39). In the Fbn1 C1039G/+ myocardium, microfibril disintegration was not associated with defective integrin signaling as indicated by the absence of dysregulation of integrin subunits β1, α5, or α9 or of the downstream effector pFAK.…”

The (dys)functional extracellular matrix

“…In one study, fibronectin–integrin adhesion force and adhesion probability increased during isolated cardiomyocyte contraction and decreased during relaxation [174]. Specific cardiac integrins (e.g., α5-β 1, αV-β 3) are essential for the heart's response to stress states and overall survival [176]. Integrin β 1 and FAK mediate mechanotransduction in the heart in response to mechanical stretch.…”

Extracellular matrix-mediated cellular communication in the heart

“…However, persistent myofibroblast activity leads to excessive accumulation of these ECM proteins and, ultimately, fibrosis. Importantly, the ECM proteins secreted from myofibroblasts serve as an intermediary network for intercellular communication by transducing intracellular signals via various cell surface receptors, often leading to the development of cardiac fibrosis, ventricular stiffening and dysfunction [3, 27, 110, 114–116] (Figure 2). In addition, ECM proteins secreted by CF are actively involved in inflammatory-mediated response following cardiac insult.…”