Integrins protect cardiomyocytes from ischemia/reperfusion injury

Abstract

Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7β1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of β1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin α7β1D exposed to I/R had a substantial reduction in infarct size compared with that of α5β1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that α7β1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca 2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca 2+ handling proteins in the CM and found that β1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165-175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that α7β1D integrin modifies Ca 2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

“…The generation of Tln1-flox, Tln2KO, MHC nuclear Cre, and the CM-specific overexpressing α7 and β1D transgenic mice has been described (16,36,57). The mice were analyzed on a mixed 129/C57BL/6 genetic background, and, unless otherwise stated, male mice that were littermate controls or from an identical genetic background were analyzed.…”

“…For this, we took advantage of the α7 and β1D transgenic mice that we had generated previously (36). Crossing the Tln1cKO/Tln2KO mouse line with the α-myosin heavy chain-α7β1D transgenic mice allowed us to generate a model that lacks both Tln1 and Tln2 in CMs, but directs cardiomyocyte-specific expression of α7β1D transgenes.…”

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

“…For example, CM-specific deletion of β1-mediated adhesion results in cardiac fibrosis and heart failure in response to pressure overload by disrupting CM membrane integrity and contractile function (Shai et al, 2002). In addition, α7β1 integrin, a laminin receptor, has also been shown to have a protective effect in CMs that are exposed to ischemic stress (Okada et al, 2013). Removal of the β1-integrin-associated mechanosensitive protein melusin (ITGB1BP2), alters signaling through ERK1/2 and glycogen synthase kinase 3β (GSK-3β), and leads to dilated cardiomyopathy and fibrosis in response to pressure overload in the heart (Brancaccio et al, 2003;Penna et al, 2014).…”

Endothelial Cells Regulate Cardiac Myocyte Reorganisation Through β1-Integrin Signalling

“…Integrin is a transmembrane heterodimeric receptor, composed of α and β subunits, that not only serves as a link between ECM ligands and cytoskeletal structures but also participates in bidirectional signal transduction associated with various biological processes, such as adhesion, spreading and migration [24]. Because integrins do not possess intrinsic kinase activity, cytoplasmic effectors must be triggered to transmit signals [25].…”

“…Recent studies have offered direct evidence for the pivotal role of β1-integrin in stress responses in the heart [24,27]. Using a mouse model featuring a cardiomyocyte-specific β1-integrin deficiency, Li et al showed that although cardiac function remained normal when β1-integrin expression was reduced to 35%, ventricular compaction was perturbed after hemodynamic stress, and this was accompanied by reduced FAK levels and alterations to multiple signalling pathways.…”