Abstract
BackgroundTransgenic (TG) mice with overexpression of an arg120gly (R120G) missense mutation in HSPB5 display desmin-related cardiomyopathy, which is characterized by formation of aggresomes. It is also known that progressive mitochondrial abnormalities and apoptotic cell death occur in the hearts of R120G TG mice. The role of mitochondrial dysfunction and apoptosis in disease progression, however, remains uncertain.Methods and ResultsMitochondrial abnormalities and apoptotic cell death induced by overexpression of HSPB5 R120G were analyzed in neonatal rat cardiomyocytes. Overexpression of mutant HSPB5 led to development of aggresomes with a concomitant reduction in cell viability in the myocytes. Overexpression of mutant HSPB5 induced a reduction in the cytochrome c level in the mitochondrial fraction and a corresponding increase in the cytoplasmic fraction in the myocytes. Down-regulation of BCL2 and up-regulation of BAX were detected in the myocytes expressing the mutant HSPB5. Concomitant with mitochondrial abnormality, the activation of caspase-3 and increased apoptotic cell death was observed. Cell viability was dose-dependently recovered in myocytes overexpressing HSPB5 R120G by treatment with nicorandil a mitochondrial ATP-sensitive potassium channel opener. Nicorandil treatment also inhibited the increase in BAX, the decrease in BCL2, activation of caspase-3 and apoptotic cell death by mutant HSPB5. To confirm the results of the in-vitro study, we analyzed the effect of nicorandil in HSPB5 R120G TG mice. Nicorandil treatment appeared to reduce mitochondrial impairment and apoptotic cell death and prolonged survival in HSPB5 R120G TG mice.ConclusionsNicorandil may prolong survival in HSPB5 R120G TG mice by protecting against mitochondrial impairments.
Highlights
The anti-anginal agent nicorandil is known as an opener of the ATP-sensitive potassium (KATP) channel with a nitrate moiety [1]
No differences of HSPB5 protein levels were seen among the cardiomyocytes infected with the wild-type HSPB5-adenovirus and the R120G-adenovirus with or without nicorandil treatment (Figure 1A and 1B)
While no difference in levels of the aggregates and amyloid oligomers were observed in the cardiomyocytes expressing R120G with nicorandil treatment, reduction in cell viability was prevented by nicorandil treatment in a dose-dependent manner (Figure 1J)
Summary
The anti-anginal agent nicorandil is known as an opener of the ATP-sensitive potassium (KATP) channel with a nitrate moiety [1]. The impact of nicorandil in angina (IONA), a randomized and placebocontrolled study, has shown that nicorandil reduced the incidence of major cardiovascular events in patients with angina pectoris [1,3]. It remains uncertain whether nicorandil has an infarct-limiting effect in humans, a great deal of attention has been attracted to molecular mechanisms by which nicorandil exerts a cardioprotective action. Besides the beneficial hemodynamic effects, such as increased coronary blood flow and reduced vascular resistance, recent studies suggest that the cardioprotective effects of nicorandil are mediated by activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels in myocytes [2,4]. The role of mitochondrial dysfunction and apoptosis in disease progression, remains uncertain
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