The Cardioprotective Role of Tissue Resident Macrophages in Cardiac Pressure Overload

Abstract

Cardiac hypertrophy is the abnormal enlargement of the myocardium in response to stress and injury. Previous studies have largely focused on the role of cardiomyocyte-intrinsic mechanisms in regulating the hypertrophic response to injury and transition to heart failure, with a recent shift in focus to the role of other cardiac cell types, including immune cells. Since cardiac fibrosis is a hallmark feature of pathological hypertrophy and a key contributor to decreased ventricular performance during pressure overload, it is important to investigate how fibrosis is regulated and how macrophages contribute to cardiac fibrosis and collagen deposition. To assess the role of macrophages in regulating the development of cardiac pressure overload-induced fibrosis, we administered CD115 blocking antibodies or isotype controls prior to transverse aortic constriction (TAC). We hypothesized that residential macrophages play a protective role in cardiac pressure overload by limiting the development of fibrosis. Flow cytometry-based assessment of cardiac immune cells showed increased abundance of macrophages at 1 week after TAC. Furthermore, we validated specific depletion of macrophages using CD115 antibodies and the data suggested preferential depletion of residential macrophages likely due to fast replenishment of bone marrow derived macrophages. Echocardiography showed no difference in cardiac function between isotype and CD115 antibody-treated mice at 1 week post-TAC, but decreased ejection fraction in CD115 antibody treated mice 6 weeks after TAC. Histological analysis showed reduced microvascular density with enhanced fibrosis and collagen deposition accompanied by increased numbers of Galectin3 expressing macrophages in CD115 antibody-treated hearts at 1 week post-TAC. At 6 weeks post-TAC, we observed increased fibrosis and collagen deposition in CD115 antibody-treated TAC mice compared to isotype controls. These results indicate that residential cardiac macrophages play a cardioprotective role in preventing fibrosis development and stimulating angiogenesis. Future studies will focus on how fibroblasts respond to macrophage activation in the setting of cardiac pressure overload.