Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II–dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II–induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF-α signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-β in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.

Key Points: A significant fraction of cell-free heme in plasma is contained in circulating erythrocyte MPs, particularly during hemolysis. Heme-laden MPs can transfer heme to vascular endothelium and mediate oxidative stress, vascular dysfunction, and vasoocclusions.

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 withGranzyme 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.