Endothelial nitric oxide synthase, vascular integrity and human exceptional longevity

Abstract

Aging is the sum of the deleterious changes that occur as time goes by. It is the main risk factor for the development of cardiovascular disease, and aging of the vasculature is the event that most often impacts on the health of elderly people. The “free-radical theory of aging” was proposed to explain aging as a consequence of the accumulation of reactive oxygen species (ROS). However, recent findings contradict this theory, and it now seems that mechanisms mediating longevity act through induction of oxidative stress. In fact, calorie restriction − a powerful way of delaying aging − increases ROS accumulation due to stimulation of the basal metabolic rate; moreover, reports show that antioxidant therapy is detrimental to healthy aging. We also now know that genetic manipulation of the insulin-like-growth-factor-1/insulin signal (IIS) has a profound impact on the rate of aging and that the IIS is modulated by calorie restriction and physical exercise. The IIS regulates activation of nitric oxide synthase (eNOS), the activity of which is essential to improving lifespan through calorie restriction, as demonstrated by experiments on eNOS knockout mice. Indeed, eNOS has a key role in maintaining vascular integrity during aging by activating vasorelaxation and allowing migration and angiogenesis. In this review, we will overview current literature on these topics and we will try to convince the reader of the importance of vascular integrity and nitric oxide production in determining healthy aging.

Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis

“…36 Based on the above observations of HSP90 recruitment by BPIFB4 and the latter being expressed in MNCs, we assessed the effect of the A/A (homozygotic major allele), A/a (heterozygotic allele), and a/a (homozygotic minor allele) genotypes of rs2070325 on the activity status of eNOS in MNCs from healthy blood donors. We found increased eNOS phosphorylation at serine 1177—an activation site of the enzyme—in a/a carriers (Figure 1).…”

Pentraxin 3 Induces Vascular Endothelial Dysfunction Through a P-selectin/Matrix Metalloproteinase-1 Pathway

“…28,29 On this point, our studies revealed that PTX3 induced an impairment in NO signaling that evoked endothelial dysfunction and enhanced smooth muscle vasoconstriction, 2 typical traits involved in increased vascular resistance in hypertension. 22 We also aimed to understand how the morphological changes observed in our study correlated with the impairment in endothelial signaling.…”

Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases

“…Jiian et al reported that resveratrol significantly reduced cytochrome C protein levels in the heart tissue of rats subjected to trauma-hemorrhage; the authors suggest that resveratrol may be important for mitochondrial membrane integrity, leading to a reduction of ROS generation (Jian et al, 2012) 2.1.3. Effects of resveratrol on nitric oxide metabolism Nitric oxide (NO) plays a critical role in maintaining cardiovascular homeostasis (Dudzinski et al, 2006;Dudzinski and Michel, 2007;Puca et al, 2012). In the vasculature, NO is constitutively synthesized by eNOS and acts by relaxing vascular smooth muscle cells and upregulating blood flow, and so prevents thrombogenic and atherogenic processes.…”