Deficiency of ataxia-telangiectasia mutated kinase modulates functional and biochemical parameters of the heart in response to Western-type diet.

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-1α1, matrix metalloproteinase (MMP)-2, and MMP-9 in WT. WD enhanced AMPK activation, while decreasing mTOR activation in hKO. Akt and IKK-α/ß 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-γ, macrophage inflammatory protein (MIP)-1α, and MIP-1ß 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.NEW & NOTEWORTHY Ataxia-telangiectasia mutated (ATM) kinase deficiency in humans associates with enhanced susceptibility to ischemic heart disease. Here, we provide evidence that ATM deficiency accelerates body weight gain and associates with increased cardiac preload, hypertrophy, and apoptosis in mice fed with Western-type diet (WD). Further investigations of the role of ATM deficiency in WD-induced alterations in function and biochemical parameters of the heart may provide clinically applicable information on treatment and/or nutritional counseling for patients with ATM deficiency.

ATM deficiency differentially affects expression of proteins related to fatty acid oxidation and oxidative stress in a sex-specific manner in response to Western-type diet prior to and following myocardial infarction.

AIMS: Published work has shown that ataxia-telangiectasia mutated kinase (ATM) deficiency is associated with cardioprotective effects in Western-type diet (WD)-fed female mice. This study assessed the expression of proteins related to fatty acid oxidation (FAO) and oxidative stress in WD-fed male and female mouse hearts, and investigated if sex-specific cardioprotective effects in WD-fed female ATM-deficient mice are maintained following myocardial infarction (MI). MAIN METHODS: Wild-type (WT) and ATM-deficient (hKO) mice (both sexes) were placed on WD for 14 weeks. Myocardial tissue from a subset of mice was used for western blot analyses, while another subset of WD-fed mice underwent MI. Heart function was analyzed by echocardiography prior to and 1 day post-MI. KEY FINDINGS: CPT1B (mitochondrial FAO enzyme) expression was lower in male hKO-WD, while it was higher in female hKO-WD vs WT-WD. WD-mediated decrease in ACOX1 (peroxisomal FAO enzyme) expression was only observed in male WT-WD. PMP70 (transports fatty acyl-CoA across peroxisomal membrane) expression was lower in male hKO-WD vs WT-WD. Catalase (antioxidant enzyme) expression was higher, while Nox4 (pro-oxidant enzyme) expression was lower in female hKO-WD vs WT-WD. Heart function was better in female hKO-WD vs WT-WD. However, post-MI heart function was not significantly different among all MI groups. Post-MI, CPT1B and catalase expression was higher in male hKO-WD-MI vs WT-WD-MI, while Nox4 expression was higher in female hKO-WD-MI vs WT-WD-MI. SIGNIFICANCE: Increased mitochondrial FAO and decreased oxidative stress contribute towards ATM deficiency-mediated cardioprotective effects in WD-fed female mice which are abolished post-MI with increased Nox4 expression.

Deficiency of ataxia-telangiectasia mutated kinase attenuates Western-type diet-induced cardiac dysfunction in female mice.

Chronic consumption of Western-type diet (WD) induces cardiac structural and functional abnormalities. Previously, we have shown that WD consumption in male ATM (ataxia-telangiectasia mutated kinase) deficient mice associates with accelerated body weight (BW) gain, cardiac systolic dysfunction with increased preload, and exacerbation of hypertrophy, apoptosis, and inflammation. This study investigated the role of ATM deficiency in WD-induced changes in functional and biochemical parameters of the heart in female mice. Six-week-old wild-type (WT) and ATM heterozygous knockout (hKO) female mice were placed on WD or NC (normal chow) for 14 weeks. BW gain, fat accumulation, and cardiac functional and biochemical parameters were measured 14 weeks post-WD. WD-induced subcutaneous and total fat contents normalized to body weight were higher in WT-WD versus hKO-WD. Heart function measured using echocardiography revealed decreased percent fractional shortening and ejection fraction, and increased LV end systolic diameter and volume in WT-WD versus WT-NC. These functional parameters remained unchanged in hKO-WD versus hKO-NC. Myocardial fibrosis, myocyte hypertrophy, and apoptosis were higher in WT-WD versus WT-NC. However, apoptosis was significantly lower and hypertrophy was significantly higher in hKO-WD versus WT-WD. MMP-9 and Bax expression, and Akt activation were higher in WT-WD versus WT-NC. PARP-1 (full-length) expression and mTOR activation were lower in WT-WD versus hKO-WD. Thus, ATM deficiency in female mice attenuates fat weight gain, preserves heart function, and associates with decreased cardiac cell apoptosis in response to WD.

Heart failure and diabetes: role of ATM.

Heart failure is a leading cause of death in the United States. Diabetes, also known as diabetes mellitus (DM), exponentially increases the risk of heart failure. The increase in oxidative stress and metabolic dysfunction caused by DM can lead to DNA damage and the development of diabetic cardiomyopathy. Ataxia telangiectasia mutated kinase (ATM) is a DNA damage response protein with a primary nuclear function to regulate cell cycle progression in response to double-strand DNA breaks, acts as a redox sensor, and facilitates DNA repair. ATM deficiency associates with the development of insulin resistance and DM. Consequently, patients with Ataxia telangiectasia, a rare autosomal recessive disorder, have an increased risk of developing heart failure. The main objective of this review is to summarize the shared metabolic and cardiac abnormalities associated with DM and ATM deficiency, with a focus on the development of heart failure.