Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.
There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1 + cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1 + cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1 + cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1 + cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1 + CD51 + cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia. Heart failure (HF) remains a leading cause of mortality and hospitalization worldwide and represents a heavy financial burden on health care systems 1-6. Current pharmacological treatments limit the peripheral consequences of cardiac dysfunction, but therapeutic approaches that impact primary adverse cardiac remodeling at the myocardial level are limited. While the etiology of HF is diverse, HF is typically associated with a range of physiological and morphological changes including fibrosis within the myocardium 7-9. Cardiac fibrosis is characterized with the excessive production and deposition of extracellular matrix (ECM) proteins within the myocardium that results in normal tissue architecture disruption, reduced tissue compliance, and mechanical and electrical dysfunction, consequently leading to HF 10,11. The mechanisms underlying cardiac fibrosis are incompletely understood, thereby impeding the development of effective anti-fibrotic therapeutics to complement the current therapies for HF 9,11,12. Activated cardiac fibroblasts are essential for the production of ECM proteins that accumulate during cardiac fibrosis; however, recent studies have established that cardiac fibroblasts represent a heterogeneous cell population 10-14. The exact nature of activated fibroblasts and consequently the sources of cardiac fibrosis remain unclear 9,12. Different mechanisms underlying fibrosis have been reported including the activation and
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