Sirtuin 1/soluble guanylyl cyclase: a nitric oxide-independent pathway to rescue ageing-induced vascular dysfunction

Extract

This editorial refers to ‘Endothelial SIRT1 prevents age-induced impairment of vasodilator responses by enhancing the expression and activity of soluble guanylyl cyclase in smooth muscle cells’ by Y. Guo et al., pp. 678–690.

Ageing, a major risk factor for the development of cardiovascular disease (CVD), causes a strong alteration of vascular homeostasis due to endothelial and smooth muscle cell dysfunction favouring a vasoconstrictor, pro-inflammatory/thrombotic state which ultimately leads to atherothrombosis.¹ Bioavailability of endothelium-derived nitric oxide (NO) represents a key marker of vascular health. The activity of L-arginine/NO pathway is a balance between synthesis and breakdown of NO by superoxide anion (O₂⁻). Under physiological conditions, NO generation via endothelial nitric oxide synthase (eNOS) is not affected by O₂⁻ and exerts its well-known vascular protective effects.² NO rapidly diffuses to the underlying vascular smooth muscle cells (VSMCs) where it activates soluble guanylyl cyclase (sGC) producing cyclic guanosine monophosphate (cGMP) and causing vasodilation.³ The initial trigger whereby ageing alters vascular function is an imbalance between NO bioavailability and accumulation of reactive oxygen species (ROS).⁴ The resulting endothelial cell (EC) dysfunction is characterized not only by decreased NO but also by increased synthesis of endothelium-derived contracting factors, in particular cyclooxygenase-2 (COX-2)-derived vasoconstrictor prostanoids, which activate the contractile process of the underlying VSMCs.⁵ The impairment of this fine-tuned control system between vasodilator and vasoconstrictor responses promotes age-dependent vascular dysfunction.⁶ A clear understanding of the molecular pathways involved in vascular ageing process is a key unmet need in cardiovascular medicine which might unveil potential novel molecular targets against age-associated CVD.