Erectile tissue molecular alterations with aging—differential activation of the p42/44 MAP Kinase pathway

Abstract

Erectile dysfunction (ED) is a common problem in aged men; however, the molecular events involved in aging ED remain unclear. To better characterize the effects of aging in the penis, we evaluated cavernosal tissue remodeling capability and the downstream activation of the intracellular signaling mediator mitogen-activated protein p42/44 kinase (p42/44 MAPK). We used male Wistar rats, which were divided in groups of 2, 6, 12, 18, and 24 months old. Penile tissues were harvested and processed for protein isolation and immunohistochemical analysis. Cavernosal viability was assessed by TUNEL assay, and proliferation was analyzed by immunohistochemical detection of proliferating cell nuclear antigen (PCNA). Immunolocalization of the activated form of p42/44 MAPK was evaluated by immunofluorescence, and changes in its phosphorylation status were quantified by western blotting. p42/44 phosphorylation profile was also assessed in situ in human young and elderly cavernosal samples. With the advancement of age, experimental cavernosal tissue remodeling was affected by an age-dependent unbalance between the rate of apoptosis and proliferation, in all erectile components. Moreover, this turnover alteration was accompanied by significant modifications in the activation profile of the downstream effector p42/44 MAPK. In the youngest corporeal samples, p42/44 was mostly activated at perivascular sites, potentially mediating cell survival/proliferation. However, in elderly experimental erectile tissue, p42/44 phosphorylation shifted to trabecular fibroblasts, indicating a potential role in extracellular matrix (ECM) production. More importantly, the same differential pattern of p42/44 activation was observed in human young and aged cavernosal fragments, suggesting a distinct function of this protein with aging. We provided evidence for the first time that with the advancement of age, there is a differential activation of p42/44 MAPK in cavernosal tissue, which may promote ECM expansion and fibrosis, therefore compromising erectile function in the elderly.

Chronic Oral Administration of the Arginase Inhibitor 2(S)‐amino‐6‐boronohexanoic Acid (ABH) Improves Erectile Function in Aged Rats

“…Furthermore, there are multiple other molecular mechanisms that have been ascertained to be responsible for age‐related ED in both preclinical and human studies that may be implicated. These include differential phosphorylation of eNOS (Musicki et al, 2005), altered corporal body structure (Bakirciorglu et al, 2001; Costa and Vendeira, 2008), increased endogenous NOS inhibitors (Imamura et al, 2007), corporal cavernosal extracellular matrix production and resultant fibrosis (Castela et al, 2011), and increased smooth muscle contractility as a result of increased RhoA/Rho‐kinase activity (Jin et al, 2006). A major limitation to this study is the lack of direct NO measurement in the rats treated with the arginase inhibitor.…”

Role of oxidative stress‐induced systemic and cavernosal molecular alterations in the progression of diabetic erectile dysfunction在糖尿病性勃起功能障碍的进展过程中氧化应激所诱导的全身以及海绵体分子变化的影响

“…Penile protein extraction and quantification was performed as described previously . Briefly, 8 μ g total protein was separated by electrophoresis on a 10% sodium dodecyl sulfate–polyacrylamide gel.…”

Dysregulated mitogen-activated protein kinase and matrix metalloproteinase in ethanol-induced cavernosal dysfunction

“…MAPK are redoxsensitive proteins, which are described to play a role in distinctive cellular events such as apoptosis, cell differentiation, contraction and matrix remodeling (Pearson et al 2001; Kwon et al 2003). Activation of the MAPK pathway is associated with hypertension-and aging-induced ED (Carneiro et al 2008;Castela et al 2011).…”