Mechanisms of Diabetic Cardiomyopathy

Abstract

CELL AND DEVELOPMENTAL BIOLOGY

Mechanisms of Diabetic Cardiomyopathy

Cassandra Awgulewitsch

Dissertation under the direction of Associate Professor Antonis K. Hatzopoulos

Type 2 Diabetes (T2D) is a prominent risk factor for cardiovascular disease linked to high mortality rates. T2D leads to non-ischemic diabetic cardiomyopathy (DCM) and the development of heart failure (HF) with preserved ejection fraction. HF incidence and severity are higher in diabetic women than diabetic men, indicating a sex-specific disparity in the progression of DCM that is poorly understood. To determine molecular mechanisms that drive DCM, we have generated and analyzed gene expression profiles in the hearts of obese and diabetic male and female db/db mice and age- and sex-matched lean controls, using RNA sequencing at three timepoints (2, 6, 12 months). We discovered a universal set of gene expression changes specific to the diabetic heart independently of sex and age, pointing to molecular mechanisms underlying deficits in metabolism and myocyte contractility and the development of pathophysiological processes such as hypertrophy, inflammation, and fibrosis. Our results further show that the cardiac response to the stress of obesity and diabetes is more rapid and robust in females compared to males. Moreover, the female response is more complex with a larger overall number of genes dysregulated in females than males, including early induction of transcriptional factors that regulate stress-related responses, inflammation, and developmental processes. Taken together, our data provide novel insights on universal and sex-specific differences in the development of DCM, pointing to new mechanisms that may be explored to improve disease outcomes in targeted ways.