Functional and molecular alterations of prostatic smooth muscle by aging in rats: role of oxidation and degradation of soluble guanylyl ciclase

Abstract

The increase in elderly population is becoming a worldwide phenomenon. Projections indicate that Brazil will be the sixth country in number of elderly people in 2020, exceeding 30 million people. Each year 650.000 elderly people are incorporated into the Brazilian population. Recent clinical studies suggest a strong relationship between aging and genitourinary tract diseases, being the benign prostatic hyperplasia (BPH) the most prevalent disease in men. Experimental studies also show a direct relationship between aging and prostatic changes; however, there are still few studies attempting to understand the pathophysiology of this association. These experimental studies have shown, in general, reduction in the nitrergic relaxation, nitric oxide (NO) production and expression of cGMP-dependent protein kinase (PKG) in aging rabbit and rodents, which can be related to higher production of reactive oxygen species (ROS) in prostate. However, these studies are still relatively scarce. A preliminary study in our laboratory evaluated the impact of aging in the prostatic smooth muscle (PSM) reactivity in middle-aged rats (9.5-month old). The contractile response to both phenylephrine (a-adrenoceptor agonist) and electrical-filed stimulation (neurogenic response) were significantly greater in prostate from middle-aged compared with young group. Aging also significantly reduced PSM relaxations induced by sodium nitroprusside (NO donor) and isoproterenol (non-selective ²-adrenoceptor agonist). These results are in accordance with epidemiological data in the literature showing a direct relationship between increased contractile response of PSM and aging, and suggest that signaling pathways such as NO-sGC-cGMP-PDE5 and adrenergic-cAMP are involved in these prostatic changes. Our hypothesis is that the hypercontractility of PSM in elderly individuals is secondary to overproduction or hyperactivation of ROS and hence decreased NO bioavailability. The local increase of ROS could lead to oxidation of heme group (Fe3+) in prosthetic group of guanylyl cyclase soluble (sGC), leading to degradation of ± and/or ² subunits of this enzyme, resulting in refractoriness to NO responses and reduced cGMP levels, thereby facilitating the PSM hypercontractility. No study has yet addressed the importance of the redox state of sGC for the PSM alterations in elderly or middle-aged individuals. Furthermore, the lower production of NO may further favour the Rho-kinase activation, which may also contribute to BPH. The present study aims to determine the role of oxidative stress e signaling pathways involved in PSM hypercontractility in middle-aged rats, emphasizing both the redox state of sGC and therapeutic values of stimulators/activators of this enzyme. We believe this study is a matter of great importance, provided the functional prostatic changes in middle age are critical to BPH development in elderly. Thus, this study can contribute positively not only to clarify the signaling pathways involved in prostate changes in middle age, as well as to offer novel therapies (sGC activators, for example) and prevention of prostate diseases. (AU)