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Cystathionine gamma-lyase is required for the heat shock protein 70-driven penile neurovascular regeneration and erectile function recovery

ABSTRACT: Neurovascular dysfunction in penis is a fundamental reason of erectile dysfunction. Diabetes mellitus is one of the major causes of erectile dysfunction and leads to a poor response to oral phosphodiesterase-5 inhibitors. Heat shock protein 70 (Hsp70), a ubiquitous molecular chaperone exist in all living organisms, is known to play a role in cell survival and neuroprotection. Here, we report an effectiveness of Hsp70 in mediating neurovascular regeneration in diabetic conditions. Using Hsp70-Tg mice or Hsp70 protein administration, we demonstrate that overexpression of Hsp70 in diabetic mice restores erectile function through enhanced penile angiogenesis and neural regeneration. We found that cystathionine gamma-lyase (Cse) is a novel target of Hsp70-driven penile angiogenesis and neural regeneration. Hsp70-Cse triggered SDF1/HO-1/PI3K/Akt/eNOS/NF-κB p65 pathways involved in angiogenesis and neural regeneration. Coimmunoprecipitation and His-Tag pull down assay using mouse cavernous endothelial cells treated with Hsp70 showed the physical interaction between Hsp70 and Cse, and solid-phase binding assay revealed a high-affinity Hsp70-Cse binding with an apparent dissociation constant of 1.8 nmol/L. We provide a novel and solid evidence for Cse-dependent mechanism of Hsp70, which mediates Hsp70-induced neurovascular regeneration and the restoration of erectile function under diabetic conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE180916 | GEO | 2022/05/11

REPOSITORIES: GEO

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Project description:Background: Erectile dysfunction (ED) is a prevalent male sexual disorder, commonly associated with hypertension, though the underlying mechanisms remain poorly understood. Objective: This study aims to explore the role of Fatty acid synthase (Fasn) in hypertension-induced ED and evaluate the therapeutic potential of the Fasn inhibitor C75. Materials and Methods: Erectile function was assessed by determining the intracavernous pressure/ mean arterial pressure (ICP/MAP) ratio, followed by the collection of cavernous tissue for transcriptomic and non-targeted metabolomic analyses. In vitro, a concentration of 10-6 M angiotensin II (Ang II) was applied to rat aortic endothelial cells (RAOECs) to establish a model of hypertension. In vivo, spontaneously hypertensive rats (SHR) were randomly divided into two groups. The SHR+C75 group received intraperitoneal injections of C75 at a dose of 2 mg/kg once a week. After five weeks of treatment, the erectile function of the rats was assessed, and penile tissues were harvested for further analysis. Molecular and protein expression were assessed using Western blotting, qRT-PCR, immunofluorescence staining, and immunohistochemistry. Results: The SHR exhibited ED, indicated by reduced maximum ICP/MAP ratios. Histologically, corpus cavernosum tissue of SHR showed elevated fibrosis and endothelial dysfunction. Additionally, increased expression of the NLRP3 inflammasome, Caspase-1, GSDMD, and the pro-inflammatory cytokines IL-1β and IL-18 was observed. Multi-omics analysis revealed significant enrichment in lipid metabolic pathways, with Fasn identified as a hub gene. In vitro, siFasn and C75 enhanced antioxidant markers Nrf2 and HO-1, reduced ROS accumulation, and suppressed NLRP3 and GSDMD levels. In vivo, C75 treatment restored endothelial function and reversed erectile dysfunction, accompanied by decreased oxidative stress and pyroptosis in the penile corpus cavernosum. Conclusion: These findings suggest that Fasn inhibition may offer a promising therapeutic strategy for hypertension-induced ED by alleviating oxidative stress and suppressing NLRP3 inflammasome-dependent endothelial cell pyroptosis via activation of the Nrf2/HO-1 pathway.

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Cystathionine gamma-lyase is required for the heat shock protein 70-driven penile neurovascular regeneration and erectile function recovery

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