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-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.
Wingard, Mary C.; Dalal, Suman; Shook, Paige L.; Myers, Rachel; Connelly, Barbara A.; Thewke, Douglas P.; Singh, Mahipal; and Singh, Krishna. 2021. Deficiency of Ataxia-Telangiectasia Mutated Kinase Modulates Functional and Biochemical Parameters of the Heart in Response to Western-Type Diet. American Journal of Physiology - Heart and Circulatory Physiology. Vol.320(6). https://doi.org/10.1152/AJPHEART.00990.2020 PMID: 33929897 ISSN: 0363-6135