Abstract 306: Mitochondrial Aldehyde Dehydrogenase, A Therapeutic Target In Post-myocardial Infarction Heart Failure In Diabetes
Development of heart failure (HF) and pathological remodeling occurs after myocardial infarction (MI). However, in diabetic patients the prognosis is far worse. Hyperglycemia leads to accumulation of reactive aldehydes like 4-hydroxy-2 nonenal (4-HNE) in the heart. 4-HNE impairs cellular function and causes organ damage by forming adducts with critical proteins. In this study, we hypothesized that 1) 4-HNE-induced impairment of mitochondrial aldehyde dehydrogenase (ALDH) i.e. ALDH2 contributed to myocardial ischemia-induced HF in diabetes mellitus (DM) and 2) pharmacological activation of ALDH2 by Alda-1 prevent post-MI cardiac damage in DM. To test these hypotheses, first 8-week old C57BLC/6J male mice were injected with streptozotocin (STZ) (150 mg/Kg). After 8 weeks of STZ, mice were infused with isoproterenol (Iso) (45 mg/Kg) for 2 weeks by mini pumps to induce chronic myocardial ischemia and HF. Cardiac dysfunction was assessed in conscious mice by echocardiography periodically until sacrifice (16 weeks after STZ). We had normal control (Con), DM control (DM), DM + Iso and non-diabetic Iso control (Iso) with n 6 in each group. Fractional shortening (FS) was reduced in DM + Iso group (47 ± 1.2%) compared to Con (53 ± 0.9 %) and DM (55 ± 1.6 %) P<0.01, but not with Iso (49 ± 1.4%). Decrease in myocardial ALDH2 activity and increase in 4-HNE adduct formation in ALDH2 and mitochondrial damage were observed in DM + Iso at various degrees compared to Con, DM and Iso. Increased cardiac fibrosis was also recorded in DM + Iso (4 ± 0.4%) relative to Con (1 ± 0.2%; P<0.001), DM (2 ± 0.1%; P<0.05) and Iso (2.4 ± 0.3%; P<0.01). In the treatment protocol, DM + Iso group were treated with Alda-1 (10mg/kg/day) from weeks 12 to 16. Alda-1 ameliorated cardiac damage in DM as evident from enhanced FS (55 ± 3.5%; P<0.01) and reduced fibrosis. Besides improving ALDH activity Alda-1 also attenuated 4-HNE adduct formation on ALDH2 and mitochondrial damage. Myocardial levels of ALDH2 activity was lower in diabetic patients with cardiomyopathy (50% reduction; P<0.007). Finally, we conclude that activation of ALDH2 ameliorates HF in diabetic mice and which has a potential to be developed as a therapeutic strategy for HF in diabetic patients.
- © 2013 by American Heart Association, Inc.