Brendan D’Souza

Introduction. The incidence of diabetes and associated mortality is increasing worldwide in both developed and developing countries, and the prevalence of heart failure in diabetic patients ranges from 19% to 26%.^2-3 Patients with diabetic cardiomyopathy are usually asymptomatic before the disease progresses.³ However, MIF increases cross-linking with collagen, causing stiffness and diastolic dysfunction.⁶ This contributes to LV dysfunction and predisposes patients to develop HF.⁶ Methods. Diabetic rats were treated with tunicamycin via intraperitoneal injection and subjected to cardiac ischemia and reperfusion. Tissues were collected and examined for pathologic injury based on PGC-1α, creatine kinase-MB (CK-MB), and cardiac troponin T (cTnT) levels.⁴ In another study, mice received intraperitoneal injections of 4-PBA to reduce cardiac ER stress after ligation of the left coronary artery (LCA). After a 4 week period, rates of ventricular aneurysm, fibrosis, and cardiac function was assessed.⁵ To assess ATF6 function, this transcription factor was knocked down or overexpressed in the cardiac myocytes of mice. The animals were then subjected to ischemia/reperfusion injury, and the oxidative stress response was measured.⁶ To determine the role ATF6, wild-type and ATF6 knockout adult murine ventricular fibroblasts were isolated from mouse hearts and treated with TGF-β. After 48 hours, fibroblast activation was assessed.⁷ Results. Preconditioning of ER stress through modulation of ATF6 and other pathways reduces ischemia and reperfusion injury. PGC-1α expression increases after pretreatment with ER stress, which may promote mitochondrial biosynthesis. Preconditioning of the ER also reduces creatine kinase-MB and cardiac troponin T levels, which is beneficial to myocytes.⁴ Reduction of ER stress inhibits cardiac remodeling and fibrosis. Cardiac rupture and remodeling can be reduced by attenuating ER stress using 4-phenylbutyric acid.⁵ Knockdown of ATF6 in cardiac myocytes increased ROS and necrotic death, and overexpression of ATF6 reduced ROS and necrotic death. Catalase, which is induced by ATF6 during ER stress, exhibited anti-oxidant properties.⁶ ATF6 demonstrated the potential to reduce the activation of cardiac fibroblast in response to TGF-β. Conversely, deletion of ATF6 may hyperactivate fibroblasts.⁷ Conclusion. Induction of ER stress during diabetic cardiomyopathy increases fibrosis and pathologic injury. Preconditioning or otherwise reducing ER stress reduces the extent of injury within myocytes. Positive control of ATF6 may be a beneficial target for diabetic patients to decrease their risk of cardiomyopathy.

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