Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

12-2021

Committee Chair or Co-Chairs

Krishna Singh

Committee Members

Mahipal Singh, Douglas Thewke, Antonio Rusinol, Thomas Ecay, Chuanfu Li

Abstract

Ataxia-telangiectasia mutated kinase (ATM), a serine/threonine kinase, plays a role in DNA damage repair, redox sensing, and metabolism. In the heart, ATM contributes significantly in the myocardial infarction (MI)-induced cardiac remodeling with effects on fibrosis, hypertrophy, apoptosis and inflammation. This study investigates the role of ATM deficiency in 14 weeks Western-type diet (WD)-induced cardiac outcomes prior to and 1-day post-MI in a sex-specific manner using wild-type (WT) and ATM heterozygous knockout (hKO) mice. In male mice, ATM deficiency induced rapid body weight gain and preload-associated dysfunction, while WT mice displayed afterload-associated dysfunction 14 weeks post-WD. Myocyte apoptosis and hypertrophy were higher in hKO-WD versus WT-WD. WD increased fibrosis, and expression of collagen-1α1, MMP-2 and MMP-9 only in WT-WD. AMPK activation was higher, while activation of mTOR and NF-kB was lower in hKO-WD versus hKO-NC. Serum levels of IL-12(p70), eotaxin, IFN-γ, MIP-1α, and MIP-1β were higher in hKO-WD versus WT-WD. Conversely, female hKO-WD mice exhibited an attenuation of weight gain and maintenance of heart function. Cholesterol, triglyceride, and glucose levels were higher in female hKO-WD. WD-induced apoptosis and Bax expression were lower in hKO-WD vs WT-WD. Collagen-1α1 expression was higher in hKO-WD vs WT-WD. MMP-2 and MMP-9 expression increased only in WT-WD. MI decreased cardiac function in both male and female mice versus their WD counterparts. The cardioprotective effects of ATM deficiency in terms of heart function were abolished in female mice 1 day post-MI. MI led to a similar infarct size and increase in apoptosis in the two WD-MI groups of both sexes. These data suggest that – 1) ATM deficiency associates with systolic and preload associated diastolic dysfunction, and exacerbates apoptosis, hypertrophy, and fibrosis in male mice in response to WD; 2) In female mice, ATM deficiency plays a cardioprotective role with preserved systolic function and decreased apoptosis in response to WD; 3) the sex-specific cardioprotective effects of ATM deficiency in females were abolished 1day post-MI. Thus, ATM deficiency affects cardiac structure and function in a sex-specific manner in response to WD and early post-MI.

Document Type

Dissertation - embargo

Copyright

Copyright by the authors.

Available for download on Sunday, January 15, 2023

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