(713.17) Deficiency of Ataxia Telangiectasia-mutated Kinase (ATM) Preserves Heart Function by Affecting Cardiac Remodeling in Response to Western-type Diet in Female Mice

Poster Board Number: E61

Paulina Ramirez (East Tennessee State University), Mary Wingard (East Tennessee State University), Paige Shook (East Tennessee State University), Suman Dalal (East Tennessee State University), Mahipal Singh (East Tennessee State University), Krishna Singh (East Tennessee State University)

Background: Western-type Diet (WD) and deficiency of ATM protein independently associate with heart disease. Previous work demonstrated that WD in male ATM deficient mice induces accelerated body weight gain and heart dysfunction (Am J Physiol Heart Circ Physiol. 2021;320:H2324-H2338). Conversely, WD in female ATM deficient mice attenuates weight gain and preserves heart function (unpublished data). Here, we investigated the mechanism by which ATM deficiency preserves heart function in female mice. It is hypothesized that ATM deficiency attenuates adverse myocardial remodeling in female mice, thereby preserving heart function.

Methods: Female wild-type (WT) and ATM heterozygous knockout (hKO) mice, aged 6 weeks, were fed with normal chow (NC) or WD for 14 weeks. Heart sections were stained with Masson’s trichrome to quantify fibrosis, TUNEL-stained to quantify apoptosis, and WGA (wheat germ agglutinin)-stained to quantify myocyte hypertrophy. Data were analyzed using ANOVA followed by Student-Newman-Keuls test.

Results: ATM deficiency associated with increased fibrosis, apoptosis (myocytes and non-myocytes) and hypertrophy in hKO-NC vs WT-NC (plt;0.05; n=4). WD significantly increased fibrosis in WT-WD mice, while no increase in fibrosis was observed in hKO-WD. WD significantly increased apoptosis in both genotypes. However, the increase in apoptosis was significantly lower in hKO-WD vs WT-WD (plt;0.05; n=4). WD increased hypertrophy in WT group. However, the hypertrophy remained significantly higher in hKO-WD vs WT-WD (plt;0.05; n=4).

Conclusion: Decrease in myocardial fibrosis and apoptosis, and increase in myocyte hypertrophy may play a role in preservation of heart function in ATM deficient female mice in response to WD.

This work is supported by National Institutes of Health (Grant numbers HL141947and HL156214) and a Merit Review award (number BX004045) from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development.