Nicotine is proved to be an important factor for
cardiac hypertrophy. Autophagy is important cell recycling system involved in the regulation of
cardiac hypertrophy.
Cilostazol, which is often used in the management of
peripheral vascular disease. However, the effects of
cilostazol on
nicotine induced autophagy and
cardiac hypertrophy are unclear. Here, we aim to determine the role and molecular mechanism of
cilostazol in alleviating
nicotine-induced cardiomyocytes
hypertrophy through modulating autophagy and the underlying mechanisms. Our results clarified that
nicotine stimulation caused cardiomyocytes
hypertrophy and autophagy flux impairment significantly in neonatal rat ventricular myocytes (NRVMs), which were evidenced by augments of LC3-II and p62 levels, and impaired autophagosomes clearance. Interestingly,
cathepsin B (CTSB) activity decreased dramatically after stimulation with
nicotine in NRVMs, which was crucial for substrate degradation in the late stage of autophagy process, and
cilostazol could reverse this effect dramatically. Intracellular ROS levels were increased significantly after
nicotine exposure. Meanwhile, p38MAPK and JNK were activated after
nicotine treatment. By using ROS scavenger N-acetyl-
cysteine (NAC) could reverse the effects of
nicotine by down-regulation the phosphorylation of p38MAPK and JNK pathways, and pretreatment of specific inhibitors of p38MAPK and JNK could restore the autophagy impairment and cardiomyocytes
hypertrophy induced by
nicotine. Moreover, CTSB activity of lysosome regained after the treatment with
cilostazol.
Cilostazol also inhibited the ROS accumulation and the activation of p38MAPK and JNK, which providing novel connection between lysosome CTSB and ROS/p38MAPK/JNK related oxidative stress pathway. This is the first demonstration that
cilostazol could alleviate
nicotine induced cardiomyocytes
hypertrophy through restoration of autophagy flux by activation of CTSB and inhibiting ROS/p38/JNK pathway, exhibiting a feedback loop on regulation of autophagy and cardiomyocytes
hypertrophy.