Hydrogen Sulfide: role, therapeutic opportunities and development of novel pharmacological tools for vascular inflamm-aging and age-related cardiovascular diseases

Cardiovascular diseases (CVDs) are the primary cause of death and disability in the elderly population with aging as a well-recognized risk factor. Vascular aging is not only characterized by a low-grade inflammation but it's often pictured as an aftereffect of the accumulation of reactive species of oxygen (ROS) that increase with age. Free radicals participate as second messengers in endothelium-dependent functions and play physiological roles. When unchecked, they contribute to alterations that lead to the manifestation of unpleasant cardiovascular events. In the last decades, studies have shown an increasing interest in endogenous gasotransmitters. Endogenous hydrogen sulfide (H2S) is identified as crucial in the regulation of cardiovascular homeostasis and its deficiency is etiologically associated with several CVD. H2S acts as a strong antioxidant, anti-inflammatory, anti-apoptotic and cytoprotective agent through the modulation of numerous intracellular signaling pathways. The aim of this study is to select and test natural compounds able to mimic H2S beneficial effects in the cardiovascular system. We did investigate the protective effects of the natural H2S-donor Erucin in vascular oxi-inflamm-aging using in vitro and ex vivo techniques. Two different cell lines (human umbilical vein endothelial and human aortic smooth muscle cells) and human arteries isolated rings were used. Cells were exposed to oxidative stress by using high levels of homocysteine (HHcy) and of hydrogen peroxide (H2O2). Cytoprotective and antioxidant effects of Erucin were evaluated, whereas, in H2O2-induced oxidative stress, the role of Erucin in modulating AMPK, Nrf2, and sirtuins pathway were investigated. Lipopolysaccharide was used as inflammatory stimuli and the anti-inflammatory effect of this compound was studied. Human aortic rings were isolated from two different subject groups, normal weighted and obese. The antioxidant and the vasodilatory effects of Erucin were investigated. Erucin preserved normal cell growth and viability by lowering total and mitochondrial ROS levels after oxidative stress stimuli. Moreover, was demonstrated that Erucin acts through modulation of three important signaling pathways: sirtuins, AMPK, and Nrf2. SIRT1 protein modulation is likely to be mediated by the inhibition of p66Shc-mediates oxidative stress. The natural H2S- donor resulted effective in protection against inflammatory stimulus through TNF-a levels reduction. Erucin prevented mitochondrial ROS production, did restore NO levels, and dilated the isolated aortic rings of obese subjects. The overall findings highlight the potential beneficial effects of Erucin and indicate this natural isothiocyanate is a suitable candidate for therapeutic/nutraceutical use in cardiovascular complications. H2S supplementation using suitable H2S-donor molecules can be an attractive pharmacological strategy