Innate Immunity and Cardiovascular Function

Brigham And Women'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Hyperglycemia induces cardiovascular complications associated with increased morbidity and mortality. The protein kinase C, polyol and advanced glycation end products (AGE) pathways are thought to be responsible for hyperglycemia-induced vascular dysfunction (i.e., loss of endothelium-dependent relaxation) and cardiomyopathy (i.e., left ventricular dysfunction, hypertrophy and cardiac fibrosis). A common feature of these three pathways is the production of reactive oxygen species, which we showed to be responsible for MBL ligand expression in ischemia/reperfusion models. We recently described augmented cardiac injury in acute hyperglycemic mice following myocardial ischemia and reperfusion. Further, acute hyperglycemia in wild type (WT) mice demonstrated loss of cardiac progenitor cells and left ventricular hypertrophy. Hyperglycemia- induced cardiac abnormalities in this acute hyperglycemia model were completely reversed in mannose- binding lectin (MBL) null mice. In the present grant application, we demonstrate that the absence of the MBL complex eliminates several key factors involved in the fibrinogenesis following acute hyperglycemia. We will also characterize the involvement of the MBL complex and complement in RAS activation. Further, we will characterize and identify the complement components involved in the expression of pro-fibrotic mediators, including RAGE, TGF-21 and galectin-3. Hyperglycemia-induced vascular and cardiac dysfunction observed after 4 days of hyperglycemia was absent in hyperglycemic MBL null mice. This proposal will further define the role of complement/MBL and the lectin complement pathway in myocardial injury, providing insight into molecular mechanisms that predispose individuals to vasculopathy and cardiomyopathy during acute hyperglycemia. Furthermore, these specific aims may subsequently lead to improved risk stratification, resource utilization and the development of novel anti-complement therapies to protect against hyperglycemic cardiovascular complications. PUBLIC HEALTH RELEVANCE: Complications from high blood glucose levels include cardiovascular complications, which are associated with increased morbidity and mortality. Using a mouse model of acute hyperglycemia, we identified a novel pathway that mediates hyperglycemia-induced vasculopathy and cardiomyopathy. Mice deficient in the innate immune molecule mannose binding lectin are protected from hyperglycemia-induced cardiac fibrogenesis, vascular dysfunction and associated cardiomyopathies.