A crucial role of ROCK for alleviation of senescence-associated phenotype

• DOI: 10.1016/j.exger.2018.02.012
• Publication Date: 2018-02-21T05:06:50Z
• Authors: Joon Tae Park; Hyun Tae Kang; Chi Hyun Park; Young-Sam Lee; Kyung A. Cho; Sang Chul Park
• Keywords: Male; 0301 basic medicine; FIBROBLASTS; Pyridines; Wound healing; 610; Senescence; ROCK inhibition; Mice; 03 medical and health sciences; Y-27632; Progeria; MITOCHONDRIA; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Fasudil; Animals; Humans; MODULATION; Child; Cellular Senescence; LIFE-SPAN; Cell Proliferation; Wound Healing; rho-Associated Kinases; CELLULAR SENESCENCE; Fibroblasts; Amides; Chromatin; Mice, Inbred C57BL; Phenotype; DNA-DAMAGE; CELLS; Chromatin remodeling genes; LIPOFUSCIN; AUTOPHAGY; RHO-KINASE

In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells. Moreover, microarray analysis revealed that the up-regulated pathway upon ROCK inhibition is enriched for chromatin remodeling genes, which may play an important role in the alleviation of senescence-associated cell cycle arrest. Indeed, ROCK inhibition induced cellular proliferation, concomitant with the amelioration of senescent phenotype. Furthermore, the restorative effect by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Taken together, our data indicate that ROCK inhibition might be utilized to ameliorate normal aging process and to treat age-related disease.