A Dual‐Acting Nitric Oxide Donor and Phosphodiesterase 5 Inhibitor Activates Autophagy in Primary Skin Fibroblasts

Abstract

Wound healing pathologies are an increasing problem in ageing societies. Chronic, non-healing wounds, which cause high morbidity and severely reduce the quality of life of affected in-dividuals, are frequently observed in aged individuals and people suffering from diseases affected by the Western lifestyle, such as diabetes. Causal treatments that support proper wound healing are still scarce. Here, we performed expression proteomics to study the effects of the small molecule TOP‐N53 on primary human skin fibroblasts and keratinocytes. TOP‐N53 is a dual‐acting nitric oxide donor and phosphodiesterase‐5 inhibitor increasing cGMP levels to support proper wound heal-ing. In contrast to keratinocytes, which did not exhibit global proteome alterations, TOP‐N53 had profound effects on the proteome of skin fibroblasts. In fibroblasts, TOP‐N53 activated the cytopro-tective, lysosomal degradation pathway autophagy and induced the expression of the selective au-tophagy receptor p62/SQSTM1. Thus, activation of autophagy might in part be responsible for ben-eficial effects of TOP‐N53.