Atorvastatin improves hyperlipidemia-induced erectile dysfunction via PKA-associated eNOS phosphorylation at the Ser633 site.

Introduction: Hyperlipidemia contributes to vasculogenic erectile dysfunction (ED) by reducing endothelial nitric oxide bioavailability. Although atorvastatin has been reported to improve ED, the upstream mechanism by which it restores endothelial nitric oxide synthase (eNOS) activity remains unclear. This study aimed to evaluate the therapeutic effect of atorvastatin in hyperlipidemia-induced erectile dysfunction (HLED) and to determine whether protein kinase A (PKA)-associated phosphorylation of eNOS at Ser633 contributes to this effect. Methods: Hyperlipidemia-induced erectile dysfunction was induced in rats by a high-fat diet. Animals received low- or high-dose atorvastatin, with tadalafil as a positive control. Erectile function, serum lipid profiles, oxidative stress, penile fibrosis, and cavernosal eNOS signaling were assessed. In parallel, oxidized low-density lipoprotein (ox-LDL)-injured rat corpus cavernosum endothelial cells (RCECs) were treated with atorvastatin in the presence or absence of the PKA inhibitor H89. Results: Atorvastatin improved dyslipidemia, reduced systemic oxidative stress, attenuated penile fibrosis, and partially restored erectile function in HLED rats. Hyperlipidemia-induced erectile dysfunction was associated with decreased eNOS phosphorylation at Ser1177 and Ser633 and increased phosphorylation at Thr495. Atorvastatin enhanced PKA activation and eNOS Ser633 phosphorylation while reducing inhibitory Thr495 phosphorylation in penile tissue. In ox-LDL-treated RCECs, atorvastatin reduced intracellular lipid and ROS accumulation and improved endothelial function, accompanied by increased PKA Thr197 and eNOS Ser633 phosphorylation. These effects were largely blunted by H89. Discussion: These findings suggest that atorvastatin ameliorates HLED by restoring endothelial function through a PKA-associated increase in eNOS Ser633 phosphorylation. This upstream endothelial mechanism may complement the action of phosphodiesterase type 5 inhibitors and provide additional benefit for hyperlipidemia-associated vasculogenic ED. The combined in vivo and in vitro design supports mechanistic relevance, although pathway inference relies partly on pharmacological inhibition with H89 and limited time-point analyses. Collectively, our results identify PKA-associated eNOS Ser633 activation as an important mechanism underlying the endothelial-protective effect of atorvastatin in HLED.