RhoA/Rho-Kinase as a Therapeutic Target for the Male Urogenital Tract

Abstract

Introduction Rho-kinase (ROCK) is a serine/threonine kinase and is one of the major downstream effectors of the small guanosine triphosphatase Rho. In the past few years, evidence has been accumulating to suggest that the RhoA/ROCK system may play an important role in the pathogenesis of a number of cardiovascular and urogenital disorders. Aim The aim of this study is to review the literature pertaining to the role of the RhoA/ROCK system in male urogenital function. Methods Comprehensive literature review was performed using PubMed. Main Outcome Measures Inhibitors of ROCK may have potential therapeutic applications, as derived from preclinical and a few clinical studies. Results Published reports suggest that elevated RhoA/Rho-kinase signaling plays a role in the development of benign prostatic hyperplasia, erectile dysfunction, kidney failure, ejaculation disorders, prostate and bladder cancer initiation, and eventual metastasis. Conclusions This review focuses on our current understanding of the role of the RhoA/Rho-kinase pathway in the regulation of the male urogenital system. Rho-kinase inhibitors may evolve into an important pharmacologic option in the future treatment of urogenital system disorders.

Implication of Rho‐kinase and soluble guanylyl cyclase enzymes in prostate smooth muscle dysfunction in middle‐aged rats

“…Increases of intracellular Ca 2+ produces smooth muscle contractions as a result of calmodulin‐mediated activation of the myosin light chain (MLC) kinase, leading subsequently to MLC phosphorylation, then producing smooth muscle contractions. Signaling mechanisms that regulate MLC phosphorylation such as RhoA/Rho‐kinase acts to increase the sensitivity of the contractile apparatus to Ca 2+ , playing critical roles in the contractile responses in many tissues, including prostate smooth muscle …”

“…Signaling mechanisms that regulate MLC phosphorylation such as RhoA/Rho-kinase acts to increase the sensitivity of the contractile apparatus to Ca 2þ , playing critical roles in the contractile responses in many tissues, including prostate smooth muscle. 4,5 Nitric oxide (NO) activates the enzyme soluble guanylyl cyclase (sGC), consequently increasing the cyclic GMP levels in vascular and non-vascular smooth muscles. Soluble guanylyl cyclase is a heterodimeric heme-containing enzyme, consisting of aand heme-containing b-subunits.…”

Icariin Combined with Breviscapine Improves the Erectile Function of Spontaneously Hypertensive Rats

“…Another approach to treat ED patients is aimed at the inhibition of pathways controlling smooth muscle contraction. Abundant evidence demonstrates that RhoA/Rho‐kinase pathway is elevated in ED of various etiologies [9]. Different Rho‐kinase inhibitors such as Y‐27632, HA‐1077, and H‐1152 improved erectile function in vitro and in vivo, and they also improved erectile function in rat models associated with ED risk factors such as aging, diabetes mellitus, hypertension, and hypogonadism [10].…”

Genomic landscape of gastric cancer: molecular classification and potential targets

“…Agents targeting RhoA itself, e.g., ROCK I, ROCK II and other effectors in the RhoA oncogenic pathways, have shown therapeutic benefits in cardiovascular disease, urogenital disorders and in other types of cancer (Gur et al, 2011;Nunes et al, 2010), suggesting a therapeutic potential for GS tumors (Sadok et al, 2015;Shang et al, 2012). The selective Rho-kinase inhibitors Y-27632 and Fasudil have been tested in pre-clinical and clinical studies (Molli et al, 2012;Olson, 2008).…”