Cardioprotective effect of nicorandil on isoproterenol induced cardiomyopathy in the Mdx mouse model

Abstract

Background Duchenne muscular dystrophy (DMD) associated cardiomyopathy is a major cause of morbidity and mortality. In an in vitro DMD cardiomyocyte model, nicorandil reversed stress-induced cell injury through multiple pathways implicated in DMD. We aimed to test the efficacy of nicorandil on the progression of cardiomyopathy in mdx mice following a 10-day treatment protocol. Methods A subset of mdx mice was subjected to low-dose isoproterenol injections over 5 days to induce a cardiac phenotype and treated with vehicle or nicorandil for 10 days. Baseline and day 10 echocardiograms were obtained to assess cardiac function. At 10 days, cardiac tissue was harvested for further analysis, which included histologic analysis and assessment of oxidative stress. Paired student’s t test was used for in group comparison, and ANOVA was used for multiple group comparisons. Results Compared to vehicle treated mice, isoproterenol decreased ejection fraction and fractional shortening on echocardiogram. Nicorandil prevented isoproterenol induced cardiac dysfunction. Isoproterenol increased cardiac fibrosis, which nicorandil prevented. Isoproterenol increased gene expression of NADPH oxidase, which decreased to baseline with nicorandil treatment. Superoxide dismutase 2 protein expression increased in those treated with nicorandil, and xanthine oxidase activity decreased in mice treated with nicorandil during isoproterenol stress compared to all other groups. Conclusions In conclusion, nicorandil is cardioprotective in mdx mice and warrants continued investigation as a therapy for DMD associated cardiomyopathy.

A Long-Term Study Evaluating the Effects of Nicorandil Treatment on Duchenne Muscular Dystrophy-Associated Cardiomyopathy in mdx Mice

“…58,64,65 Our lab has previously modeled DMD cardiomyopathy using low dose isoproterenol to induce cardiac injury and found this model sufficiently unmasks the cardiac defect present in young mdx but not WT mice. 15 Recently, we examined the effects of short-term nicorandil treatment on isoproterenol-induced cardiac injury in young mdx mice. 15 This short-term study demonstrated that nicorandil treatment in young mdx mice rescued isoproterenol-induced cardiac injury through improving % EF and FS, diminishing cardiac fibrosis and enhancing antioxidant levels (Table 3).…”

“…15 Recently, we examined the effects of short-term nicorandil treatment on isoproterenol-induced cardiac injury in young mdx mice. 15 This short-term study demonstrated that nicorandil treatment in young mdx mice rescued isoproterenol-induced cardiac injury through improving % EF and FS, diminishing cardiac fibrosis and enhancing antioxidant levels (Table 3). That study served as the rationale for us to examine whether long-term nicorandil treatment could also be cardioprotective.…”

“…Since nicorandil has previously been shown to stimulate antioxidant activity and diminish oxidative stress in the heart, 14,15,37,38 we next examined the levels of antioxidant SOD2, as well as the levels of pro-oxidant NOX4 in 15 month mdx hearts. We sought to establish whether there were any cellular alterations that had occurred, despite the lack of functional cardiac improvement (Table 1).…”

“…One potential drug that has recently demonstrated beneficial effects in the DMD heart is nicorandil, vasodilatory drug most often used to treat angina. [14][15][16] Nicorandil is a pleotropic drug that modulates NO signaling, 17 acts as an antioxidant, 14,18,19 and improves mitochondrial health by stimulating kATP channel activity. 20 Since deficiencies in these cellular processes have been ascribed to DMD cardiac pathology, [21][22][23][24] nicorandil represents an attractive therapeutic option warranting further study.…”

“…14 In vivo, nicorandil was shown to protect mdx hearts from fibrotic injury through enhancing antioxidant activity as evidenced by increased SOD2 levels, and diminished nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and xanthine oxidase (XO) activity. 15 Here, we investigated whether nicorandil would be cardioprotective long-term against the cardiomyopathy that can naturally occur in aging mdx mice. 25 Young, 11-week old female mdx mice were aged to 15 months to allow for the DMD-associated cardiac defect to manifest and nicorandil supplementation began at 3 months.…”