MICROMouse Program Application Abstract
Characterization of A New Murine Model of Cardiomyopathy in Type 2 Diabetes
Kevin O'Brien (Seattle, WA)
Patients with diabetes have an approximately 2-fold increase in risk for congestive heart failure (CHF), CHF hospitalizations and non-ischemic cardiomyopathy. Understanding the mechanisms underlying this diabetes-associated cardiomyopathy would be facilitated greatly by the availability of robust murine models. The Animal Models of Diabetic Complications Consortium (AMDCC) has published three criteria for validation of a murine model of cardiomyopathy in Type 2 diabetes: 1) cardiac hypertrophy, 2) systolic and/or diastolic cardiac dysfunction, and 3) cardiomyocyte hypertrophy and fibrosis; however, to date no mouse models have fulfilled all AMDCC criteria. Our preliminary data suggest that superimposition of genetic leptin-deficiency (ob/ob genotype) on the black and tan brachyuric (BTBR) inbred mouse strain is associated with significant increases in cardiac hypertrophy and fibrosis, as well as diastolic dysfunction. We propose to validate the BTBR ob/ob model, by AMDCC cardiomyopathy criteria, and to preliminarily investigate specific molecular pathways that may participate in disease pathogenesis. To accomplish these goals, we propose the following Specific Aims: 1) Quantify cardiac hypertrophy, increased myocyte size and cardiac fibrosis, and determine the time-course of development of these changes BTBR ob/ob and WT mice at 8, 16 and 22 weeks of age. 2) To validate the additional AMDCC criterion of cardiac dysfunction, we will perform; a) at 8, 16 and 22 weeks of age, both standard 2-dimensional echocardiography to quantify LV chamber size, thickness, mass, ejection fraction and cardiac output; as well as novel, echocardiography-based strain and strain rate analyses of systolic and diastolic function, and b) at 22 weeks, LV function also will be assessed using the "gold standard" of invasive left ventricular catheterization. 3) To preliminarily investigate the roles of molecular pathways in disease development, we will use histochemical and immunohistochemical techniques to quantify capillary density and apoptosis (TUNEL, caspase-3 assays), and RT-PCR to quantify expression of fibrosis mediators (TGF-beta and CTGF) and renin-angiotensin-aldosterone system components.
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