World J Mens Health.  2022 Oct;40(4):580-599. 10.5534/wjmh.210249.

Heat Shock Protein 70 in Penile Neurovascular Regeneration Requires Cystathionine Gamma-Lyase

• Ghatak K
• Yin GN
• Hong SS
• Kang JH
• Suh JK
• Ryu JK

• KMID: 2537107
• DOI: http://doi.org/10.5534/wjmh.210249

Abstract

Purpose
Diabetes mellitus, one of the major causes of erectile dysfunction, leads to a poor response to phosphodiesterase-5 inhibitors. Heat shock protein 70 (Hsp70), a ubiquitous molecular chaperone, is known to play a role in cell survival and neuroprotection. Here, we aimed to assess whether and how Hsp70 improves erectile function in diabetic mice.
Materials and Methods
Eight-week-old male C57BL/6 mice and Hsp70-Tg mice were used in this study. We injected Hsp70 protein into the penis of streptozotocin (STZ)-induced diabetic mice. Detailed mechanisms were evaluated in WT or Hsp70-Tg mice under normal and diabetic conditions. Primary MCECs, and MPG and DRG tissues were cultivated under normalglucose and high-glucose conditions.
Results
Using Hsp70-Tg mice or Hsp70 protein administration, we demonstrate that elevated levels of Hsp70 restores erectile function in diabetic mice. We found that cystathionine gamma-lyase (Cse) is a novel target of Hsp70 in this process, showing that Hsp70-Cse acts through the SDF1/HO-1/PI3K/Akt/eNOS/NF-κB p65 pathway to exert its neurovascular regeneration-promoting effects. Coimmunoprecipitation and pull-down assays using mouse cavernous endothelial cells treated with Hsp70 demonstrated physical interactions between Hsp70 and Cse with a dissociation constant of 1.8 nmol/L.
Conclusions
Our findings provide novel and solid evidence that Hsp70 acts through a Cse-dependent mechanism to mediate neurovascular regeneration and restoration of erectile function under diabetic conditions.

Keyword

Cystathionine gamma-lyase; Diabetes mellitus; Erectile dysfunction; Heat shock protein 70; Neovascularization; Nerve regeneration