Cardiovascular diseases are the leading cause of mortality worldwide. Ataxia telangiectasia mutated kinase (ATM) is a checkpoint protein involved in cell cycle regulation. It is activated in response to genotoxic mediators such as double-stranded DNA damage or oxidative damage. Mutations in the ATM gene result in a multisystemic disease called ataxia-telangiectasia (A-T). Independently, a Western-type Diet (WD) and ATM protein deficiency are linked with heart disease, exacerbated cardiac remodeling, and myocardial infarction (MI). Our laboratory has previously shown that in male mice, the consumption of a WD during ATM deficiency is associated with the exacerbation of cardiac remodeling. This study investigated the effect of ATM deficiency on WD-induced cardiac remodeling parameters before and 1-day post-MI in a sex-specific manner using female and male mice. Age-matched wild-type (WT) and ATM heterozygous knockout (hKO) mice were fed with normal-chow (NC) or WD for 14 weeks. MI was induced by ligation of the left anterior descending coronary artery (LAD) with a 7-0 polypropylene suture. After the study period, 14 weeks post-WD feeding and 1-day post-MI, the heart was removed through an opening in the diaphragm region. Heart sections were stained with Masson's trichrome to quantify fibrosis, TUNEL-stained to quantify apoptosis, infarct size, and infarct thickness, and wheat germ agglutinin-stained to quantify myocyte hypertrophy. In WT female mice, WD increased myocardial fibrosis, myocyte hypertrophy, and apoptosis at baseline compared to NC. However, in hKO-WD female mice, apoptosis was significantly lower, and hypertrophy was significantly higher than in WT-NC female mice at baseline. Intriguingly, no significant difference in apoptosis, infarct size, and infarct thickness was observed in both genotypes and genders 1-day post-MI. Thus, our data suggest that 1) ATM deficiency plays a cardioprotective role in female mice responding to WD, as it reduces apoptosis and increases hypertrophy at baseline, and 2) sex-specific cardioprotective effects of ATM deficiency in female mice were not observed 1-day post-MI in response to WD.

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.

Ataxia-telangiectasia mutated (ATM) kinase deficiency exacerbates heart dysfunction late after myocardial infarction. Here, we hypothesized that ATM deficiency modulates Western-type diet (WD)-induced cardiac remodeling with an emphasis on functional and biochemical parameters of the heart. Weight gain was assessed in male wild-type (WT) and ATM heterozygous knockout (hKO) mice on weekly basis, whereas cardiac functional and biochemical parameters were measured 14 wk post-WD. hKO-WD mice exhibited rapid body weight gain at weeks 5, 6, 7, 8, and 10 versus WT-WD. WD decreased percent fractional shortening and ejection fraction, and increased end-systolic volumes and diameters to a similar extent in both genotypes. However, WD decreased stroke volume, cardiac output, peak velocity of early ventricular filling, and aortic ejection time and increased isovolumetric relaxation time (IVRT) and Tei index versus WT-NC (normal chow). Conversely, IVRT, isovolumetric contraction time, and Tei index were lower in hKO-WD versus hKO-NC and WT-WD. Myocyte apoptosis and hypertrophy were higher in hKO-WD versus WT-WD. WD increased fibrosis and expression of collagen-1a1, matrix metalloproteinase (MMP)-2, and MMP-9 in WT. WD enhanced AMPK activation, while decreasing mTOR activation in hKO. Akt and IKK-a/b activation, and Bax, PARP-1, and Glut-4 expression were higher in WT-WD versus WT-NC, whereas NF-κB activation and Glut-4 expression were lower in hKO-WD versus hKO-NC. Circulating concentrations of IL-12(p70), eotaxin, IFN-c, macrophage inflammatory protein (MIP)-1a, and MIP-1b were higher in hKO-WD versus WT-WD. Thus, ATM deficiency accelerates weight gain, induces systolic dysfunction with increased preload, and associates with increased apoptosis, hypertrophy, and inflammation in response to WD.