Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide.

AIMS: Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. METHODS AND RESULTS: Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. CONCLUSION: Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

Targeting TRPV1 and TRPV2 for potential therapeutic interventions in cardiovascular disease.

Cardiovascular disease is a leading cause of morbidity and mortality worldwide, encompassing a variety of cardiac and vascular conditions. Transient receptor potential vanilloid (TRPV) channels, specifically TRPV type 1 (TRPV1) and TRPV type 2 (TRPV2), are relatively recently described channels found throughout the body including within and around the cardiovascular system. They are activated by a variety of stimuli including high temperatures, stretch, and pharmacologic and endogenous ligands. The TRPV1 channel has been found to be an important player in the pathway of the detection of chest pain after myocardial injury. Activation of peripheral TRPV1 via painful stimuli or capsaicin has been shown to have cardioprotective effects, whereas genetic abrogation of TRPV1 results in increased myocardial damage after ischemia and reperfusion injury in comparison to wild-type mice. Furthermore, blood pressure changes have been noted upon TRPV1 stimulation. Similarly, the TRPV2 channel has also been associated with changes in blood pressure and cardiac function depending on how and where the channel is activated. Interestingly, overexpression of TRPV2 channels in the heart induces dystrophic cardiomyopathy; however, stimulation under physiologic conditions leads to improved cardiac function. Probenecid, a TRPV2 agonist, has been studied as a model therapy for its inotropic effects and potential use in the treatment of cardiomyopathy. In this review, we present an up to date account of the growing evidence that supports the study of TRPV1 and TRPV2 channels as targets for therapeutic agents of cardiovascular diseases.