Cumulative Effect of Cardiovascular Risk Factors on Regulation of AMPK/SIRT1-PGC-1α-SIRT3 Pathway in the Human Erectile Tissue

Abstract

Cardiovascular disease risk factors (CVDRF), especially diabetes mellitus (DM), disrupt oxidative stress response. This condition underlies endothelial dysfunction, early manifested in men as erectile dysfunction. The current study is aimed at elucidating the impact of CVDRF in the oxidation responsive AMPK/SIRT1-PGC-1α-SIRT3 pathway and related miRNAs in the human corpus cavernosum. Human penile tissue fragments from individuals submitted to programmed urological surgeries (n=27), aged 43-63 years, were clustered depending on the presence of CVDRF; the control group included samples from patients without CVDRF, and groups A and B included samples from patients with DM and additional CVDRF, totalizing ≤2 CVDRF (group A) and ≥3 CVDRF (group B). Dual-immunolabelling of SIRT3, SOD2, or GPX1 with α-actin in tissue sections was carried out. The assessment of expression levels of NOX1, phospho-AMPKα, total AMPKα, SIRT1, PGC-1α, SIRT3, SOD2, and GPX1 was performed by western blotting and of miR-200a, miR-34a, miR-421, and miR-206 by real-time PCR. Phospho-AMPKα and SIRT3 expression was found significantly increased in group B relative to other groups, suggesting a marked influence of CVDRF, additional to DM, in the regulation of these enzymes. NOX1 was also increased in group B relative to controls. Only an increasing tendency was observed in the phospho-AMPKα/total AMPKα ratio, SIRT1, and PGC-1α expression in groups A and B when compared with controls. Concerning antioxidant enzymes, GPX1 expression was found incremented in group A, but SOD2 expression was decreased in groups A and B, comparative with controls. Group B presented significantly diminished levels of miR-421 and miR-200a, but only a decreasing trend on miR-34 and miR-206 expression was observed. Taken together, our findings demonstrated that besides DM, additional CVDRF presented a cumulative effect in the cellular response to oxidative unbalance, contributing to AMPK/SIRT1-PGC-1α-SIRT3 pathway activation. SOD2, a major mitochondrial antioxidant defence, did not follow the same variation.

Effect of icariin on the H2O2-induced proliferation of mouse airway smooth muscle cells through miR-138-5p regulating SIRT1/AMPK/PGC-1α axis

“…It exerts an antioxidative stress effect, thereby protecting against myocardial ischemic injury. 33 , 34 Moreover, SIRT1 can inhibit NF-κB activity by inducing AMPK and PGC-1α activities. 35 It regulates the inflammatory and oxidative stress responses induced by various factors.…”

Melatonin postconditioning combined with sitagliptin exerts full cardioprotection in diabetic hearts of aged rats through an AMPK-dependent mechanism

“…The AMPK/SIRT1 pathway plays a key role in cell survival and mitochondrial homeostasis in cardiac cells [6,9]. This pathway also has antidiabetic and anti-aging benefits in addition to having cardioprotective effects [30].…”

“…Thus, augmentation of apoptotic injuries and oxidative stress in the aged diabetic heart requires treatments that, while having potent antidiabetic effects, can overcome these sequential negative events and provide full protection of the heart against IR damage. Metabolic changes due to diabetes and aging reduce the activity of AMP-activated kinase (AMPK) and its downstream target sirtuin-1 (SIRT1) [6]. AMPK and SIRT1 both act as energy (fuel) sensors and share common intracellular targets [7].…”

“…AMPK and SIRT1 both act as energy (fuel) sensors and share common intracellular targets [7]. Activation of the AMPK/SIRT1 pathway promotes or regulates important biological functions such as cellular longevity, mitochondrial function, autophagy and reduction of oxidative stress and apoptosis [6,7]. The association of the AMPK/SIRT1 pathway with cardioprotection in ischemic heart without risk factors has been well documented [8,9].…”

Kai-Xin-San protects against mitochondrial dysfunction in Alzheimer's disease through SIRT3/NLRP3 pathway

“…Multiple mechanisms linked with AD pathophysiology, as APP processing, Tau protein aggregation, mitochondrial disorders, neuroin ammation, and oxidative damage, could be modulated by SIRTs [18,19]. Mitochondrial sirtuin 3 (SIRT3), a mitochondrial deacetylase, is essential for energy balance, mitochondrial biogenesis, and oxidative stress regulation [20]. Downregulation of SIRT3 in AD patients' brains has been documented [21]and experimental AD mouse models [22].…”