MerTK as a new target to understand and ameliorate HFpEF

点击翻译按钮获取中文摘要

Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) is an epidemic and the incidence is continuing to rise. Despite the prevalence of HFpEF, classical heart failure treatments and novel drug targets have failed to elucidate an effective therapy. HFpEF is characterized by “damage from without” the myocardium with extra- cardiac comorbidities such as obesity, hypertension and metabolic syndrome. A chronic state of systemic low- grade inflammation induces reactive oxygen species (ROS) production in endothelial cells and nitrosative stress. This culminates in impaired cardiomyocyte relaxation preventing proper filling of the left ventricle and reduced cardiac reserve. The innate immune system is a driving force behind HFpEF. As a result of systemic inflammation, monocyte migration into the sub-endothelium is promoted by upregulations in vascular cell adhesion molecule (VCAM) and E-selectin on endothelial cells. Additionally, cardiac biopsies of HFpEF patients show elevations in the pro-fibrotic cytokine transforming growth factor (TGF)-β. Along with observed increased cardiac fibrosis, this suggests a role for the activation of macrophages (Mɸ), however, their exact function in HFpEF pathophysiology is unknown. Clinically, elevations in the solubilized form of Mɸ anti-inflammatory receptor MerTK (solMER) have led us to explore its function in HFpEF. MerTK plays an important role in maintaining tissue homeostasis through phagocytosis of apoptotic cells (efferocytosis). However, MerTK also plays a role in cell survival, lipid uptake, and inflammation resolution. MerTK has previously been implicated in cardiac repair after ischemic injury by promoting phagocytosis of dying cardiomyocytes. Interestingly, in contrast to ischemic injury, our preliminary data suggest that MerTK may be promoting HFpEF instead of acting in its usual cardioprotective role. Specifically, this proposal hypothesizes that Mɸ MerTK exacerbates the development or persistence of HFpEF through the promotion of excessive MerTK-stimulated cardiac fibrosis triggered by the combined HFpEF risk factors of high fat and nitrosative stress. This hypothesis will be tested using mouse models of HFpEF in combination with MerTK knockout and inhibition. Mechanism-specific questions will be supplemented with in vitro gene expression characterization. The proposed studies will identify a potential new drug target for treatment and prevention of HFpEF, something desperately needed in clinic.