Genetic inhibition of the UPR gene Chac1 preserves cardiac function in a murine model of pressure overload induced heart failure

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Introduction: The Unfolded Protein Response (UPR) is induced accompanying endoplasmic reticulum (ER) stress in cardiac myocytes, and has been implicated in the development of heart failure. Chac1 is a UPR induced gene, which directs enzymatic cleavage of intracellular glutathione and promotes cell death. Ablation of the Chac1 gene (Chac1-/-) in mice is lethal, whereas Chac1 heterozygous (Chac1+/−) mice were produced and are viable. Purpose: To investigate the effects of Chac1 haplo-insufficiency on cardiac structure and function in mice, in the setting of heart failure after aortic banding. Methods and Results: Chac1+/− and control (WT) mice (n ≥ 12) were subjected to aortic banding to induce pressure overload heart failure. After banding, the extent of cardiac dysfunction was evaluated using 2-D echocardiography, including ventricular hypertrophy and reduced cardiac output. At baseline, we found Chac1+/− mice had cardiac hypertrophy and increased ejection fraction (70 ±1 % vs 61 ±1 %, p < 0.01) compared to WT. Querying early time points 6-9 weeks after aortic banding, a parallel hypertrophic response occurred in Chac1+/− vs controls. Notably, by 15 weeks after aortic banding Chac1+/− mice had preserved cardiac ejection fraction (58±4 vs 36±2%, p < 0.01) compared to WT that had progressed into heart failure. Chac1+/− mice also displayed attenuated chamber dilation (LVEDD: 3.9 ±0.1 vs 4.5 ±0.1 mm p <0.01), lower normalized cardiac mass (9.6 ±0.3 vs 10.9 ±0.5, p<0.05), and reduced pulmonary edema (99 ±6 vs 120 ±3 mg fluid). Examining cardiac ventricle mRNA expression 15 weeks after TAC, Chac1+/− mice showed decreased Nppb (BNP), MLC2v, and Pin1 expressions versus WT. Conclusions: A benefit for Chac1 haplo-sufficiency in mice accompanying heart failure is revealed, evidenced by preserved cardiac structure and function. Additionally, Chac1+/− mice have increased cardiac mass and enhanced function at baseline, mimicking exercise-induced cardiac hypertrophy. Chac1 inhibition may represent a novel therapeutic strategy for heart failure, phenocopying the cardiac benefits of exercise.