Abstract
Optimal healing after myocardial infarction requires not only the induction of inflammation, but also its timely resolution. In patients, 30 days post myocardial infarction, circulating monocytes have increased expression of Semaphorin3A (Sema3A) as compared to directly after admission. This increased expression coincides with increased expression of Cx3CR1—a marker of non-classical monocytes that are important for immune resolution hence proper wound healing. In mice, the expression of Sema3A also increases in response to myocardial ischemia being expressed by infiltrating leukocytes. Comparing Sema3A heterozygote (HZ) and wild type (WT) mice post myocardial infarction, revealed increased presence of leukocytes in the cardiac tissues of HZ mice as compared to WT, with no differences in capillary density, collagen deposition, cardiomyocyte surface area, chemokine—or adhesion molecules expression. Whilst infarct sizes were similar 14 days after myocardial infarction in both genotypes, Sema3A HZ mice had thinner infarcts and reduced cardiac function as compared to their WT littermates. In vitro experiments were conducted to study the role of Sema3A in inflammation and resolution of inflammation as a potential explanation for the differences in leukocyte recruitment and cardiac function observed in our in vivo experiments. Here, recombinant Sema3A protein was able to affect the pro-inflammatory state of cultured bone marrow derived macrophages. First, the pro-inflammatory state was altered by the induced apoptosis of classical macrophages in the presence of Sema3A. Second, Sema3A promoted the polarization of classical macrophages to resolution-phase macrophages and enhanced their efferocytotic ability, findings that were reflected in the infarcted cardiac tissue of the Sema3A HZ mice. Finally, we demonstrated that besides promoting resolution of inflammation, Sema3A was also able to retard the migration of monocytes to the myocardium. Collectively our data demonstrate that Sema3A reduces cardiac inflammation and improves cardiac function after myocardial infarction by promoting the resolution of inflammation.
Highlights
The improved clinical management of acute myocardial infarction (AMI) has resulted in a substantial reduction in mortality, yet this has led to the increased prevalence of heart failure and represents a huge socio-economic burden [23]
We further addressed the effect of Sema3A on macrophage function, as timely resolution of cardiac inflammation is a vital step in proper cardiac healing in response to ischemia
It is the first study to demonstrate a role for Sema3A in promoting the resolution of inflammation after AMI which may be in line with the increased expression of Sema3A in monocytes of human subjects following myocardial infarction
Summary
The improved clinical management of acute myocardial infarction (AMI) has resulted in a substantial reduction in mortality, yet this has led to the increased prevalence of heart failure and represents a huge socio-economic burden [23]. Cardiac inflammation in response to ischemia is key for repairing the damaged myocardium yet sustained inflammation results in adverse remodeling and 42 Page 2 of 13. Post-infarct inflammation promotes infarct healing granted in its containment via the timely clearance of recruited pro-inflammatory leukocytes [16, 32]. The signals that recruit pro-inflammatory monocytes (LyChi) has been well characterized [30], but little is known about the factors that switch off inflammation [2]. Recent studies have introduced the possibility that the transition to repair is not solely driven by the recruitment of reparative monocytes from the circulation, but suggest that local factors may be a key in promoting resolution from within the heart [18]. Understanding the molecular mechanisms that underline the transition to repair is important in designing new effective therapeutic strategies
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