Shot through the heart (cell membrane)
Reintroduction of oxygenated blood into the heart following an ischemic event induces inflammation that results in cardiomyocyte (CM) death. Integrins are transmembrane receptors that are part of the extracellular matrix (ECM), and relay information about changes in the ECM into the cell. Hideshi Okada and colleagues at the University of California San Diego examined the role of integrins in cardiomyocyte death as a result of the reperfusion of oxygenated blood following ischemia. The authors found that CM-specific integrins were upregulated in response to ischemia and reperfusion and overexpression of these integrins in mice resulted in reduced levels of damage following ischemia and reperfusion. Furthermore, CM-associated integrins stabilized the calcium release channel and reduced injurious changes in mitochondrial Ca2+. This study indicates that therapies that promote CM integrin upregulation or Ca2+ balance may provide protection against reperfussion-associated damage following ischemia. The above cartoon depicts heterodimeric integrin receptors (lightening-like appearance) traversing the cardiac myocyte sarcolemmal membrane. Outside the cell the integrin binds to extracellular matrix (clouds). In the cell cytoplasm (sarcoplasm) the β1D integrin subunit cytoplasmic tail complexes to the calcium release channel (ryanodine receptor 2 (RyR2)) embedded in the sarcoplasmic reticulum. Calcium (small round spots near the integrin cytoplasmic tail) is noted adjacent to the RyR2.
Related articles
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 Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ 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 Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.
Authors
Hideshi Okada, N. Chin Lai, Yoshitaka Kawaraguchi, Peter Liao, Jeffrey Copps, Yasuo Sugano, Sunaho Okada-Maeda, Indroneal Banerjee, Jan M. Schilling, Alexandre R. Gingras, Elizabeth K. Asfaw, Jorge Suarez, Seok-Min Kang, Guy A. Perkins, Carol G. Au, Sharon Israeli-Rosenberg, Ana Maria Manso, Zheng Liu, Derek J. Milner, Stephen J. Kaufman, Hemal H. Patel, David M. Roth, H. Kirk Hammond, Susan S. Taylor, Wolfgang H. Dillmann, Joshua I. Goldhaber, Robert S. Ross
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)