Abstract
Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p < 0.05). Mitochondrial respiration was reduced by DiMAL 0.6 mM compared to sham and DiMAL 0.1 mM (p < 0.05). In diabetic hearts an increased concentration of DiMAL (0.6 mM) was required for protection compared to IR (64 ± 13% vs. 79 ± 8%, p < 0.05). Mitochondrial function remained unchanged. In trabeculae from humans without diabetes, IPC and DiMAL improved contractile force recovery compared to IR (43 ± 12% and 43 ± 13% vs. 23 ± 13%, p < 0.05) but in patients with diabetes only IPC provided protection compared to IR (51 ± 15% vs. 21 ± 8%, p < 0.05). Neither IPC nor DiMAL modulated mitochondrial respiration in patients. Cardioprotection by SDH inhibition is possible in human tissue, but depends on diabetes status. The narrow therapeutic range and discrepancy in respiration between experimental and human studies may limit clinical translation.
Highlights
Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL)
The main finding of the present study is that inhibition of the SDH by administration of DiMAL protects the heart from IR injury in non-diabetic and diabetic animals
Diabetes seems to reduce the sensitivity to DiMAL such that an increased dose is required to elicit a cardioprotective response
Summary
Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). We transferred these findings into human cardiac tissue by examining the effect of pre-ischemic SDH inhibition by DiMAL on contractile force recovery and mitochondrial function in trabeculae from patients with or without type 2 diabetes. At the end of the perfusion protocol in experimental series II of the isolated rat heart study, the left ventricle was quickly divided in two samples during continued perfusion for subsequent measurement of mitochondrial respiration and various tissue analyses.
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