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 mannose binding lectin (MBL) ligand expression in ischemia/reperfusion (I/R) models. We recently described augmented cardiac injury in acute hyperglycemic mice following myocardial I/R. Further, acute hyperglycemia in wild type (WT) mice caused a loss of cardiac progenitor cells and the development of left ventricular hypertrophy. Hyperglycemia-induced cardiac abnormalities in this acute hyperglycemia model were completely reversed in MBL null mice. In the present grant, we demonstrate that the absence of the MBL complex or complement inhibition eliminates several key factors involved in the cardiac fibrinogenesis, vascular dysfunction, and inflammation following acute hyperglycemia. This grant will characterize the role of each complement pathway (classical, alternative, lectin and terminal) in the vasculopathy and cardiomyopathy induced by acute hyperglycemia. We will also characterize the involvement of the MBL complex and complement in renin-angiotensin system (RAS) activation and cardiac autophagy. While cardiac autophagy can be adaptive or maladaptive, little is known about cardiac autophagy in hyperglycemia and no interactions with complement have been investigated. We propose that complement activation leads to cardiac autophagy and represents a centralized nexus for pro-fibrotic mediator production including RAGE, TGF-21 and galectin- 3. This proposal will continue our laboratory's general focus on the complement system and myocardial function by investigating the 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089781-03
Application #
8586247
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Davidson, Wendy F
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$508,864
Indirect Cost
$193,864
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Pavlov, Vasile I; Tan, Ying S; McClure, Erin E et al. (2015) Human mannose-binding lectin inhibitor prevents myocardial injury and arterial thrombogenesis in a novel animal model. Am J Pathol 185:347-55
Tong, Hua Hua; Lambert, Garrett; Li, Yong Xing et al. (2014) Deletion of the complement C5a receptor alleviates the severity of acute pneumococcal otitis media following influenza A virus infection in mice. PLoS One 9:e95160
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Pavlov, Vasile I; Skjoedt, Mikkel-Ole; Siow Tan, Ying et al. (2012) Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis. Circulation 126:2227-35
Pavlov, Vasile I; La Bonte, Laura R; Baldwin, William M et al. (2012) Absence of mannose-binding lectin prevents hyperglycemic cardiovascular complications. Am J Pathol 180:104-12

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