Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease—From Bench to Bedside

Abstract

Sirtuins (SIRT1–7) comprise a family of highly conserved deacetylases with distribution in different subcellular compartments. Sirtuins deacetylate target proteins depending on one common substrate, nicotinamide adenine diphosphate (NAD+), thus linking their activities to the status of cellular energy metabolism. Sirtuins had been linked to extending life span and confer beneficial effects in a wide array of immune-metabolic and cardiovascular diseases. SIRT1, SIRT3, and SIRT6 have been shown to provide protective effects in various cardiovascular disease models, by decreasing inflammation, improving metabolic profiles or scavenging oxidative stress. Sirtuins may be activated collectively by increasing their co-substrate NAD+. By supplementing NAD+ precursors, NAD+ boosters confer pan-sirtuin activation with protective cardiometabolic effects in the experimental setting: they improve endothelial dysfunction, protect from experimental heart failure, hypertension and decrease progression of liver steatosis. Different precursor molecules were applied ranging from nicotinamide (NAM), nicotinamide mononucleotide (NMN) to nicotinamide riboside (NR). Notably, not all experimental results showed protective effects. Moreover, the results are not as striking in clinical studies as in the controlled experimental setting. Species differences, (lack of) genetic heterogeneity, different metabolic pathways, dosing, administration routes and disease contexts may account for these challenges in clinical translation. At the clinical scale, caloric restriction can reduce the risks of cardiovascular disease and raise NAD+ concentration and sirtuin expression. In addition, antidiabetic drugs such as metformin or SGLT2 inhibitors may confer cardiovascular protection, indirectly via sirtuin activation. Overall, additional mechanistic insight and clinical studies are needed to better understand the beneficial effects of sirtuin activation and NAD+ boosters from bench to bedside.

Supplementation with a Cocoa–Carob Blend, Alone or in Combination with Metformin, Attenuates Diabetic Cardiomyopathy, Cardiac Oxidative Stress and Inflammation in Zucker Diabetic Rats

“…Therefore, the reduced oxidative stress and increased antioxidant activity induced by the mix of flavonoids presented in CCB could be mediated by the sirtuin pathway, as proven in in vitro and in vivo studies [ 38 , 46 , 47 , 49 ]. Interestingly, several studies have identified other sirtuins (mainly SIRT3 and SIRT6) to provide beneficial effects in cardiovascular diseases and energy metabolism [ 50 ]. Accordingly, a very recent report described the protective effect of the flavone acacetin against cardiac senescence via SIRT1-mediated activation of SIRT6/AMPK signalling pathway [ 51 ].…”

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

“…To clarify this hypothesis, it should be noted that elevated levels of NAD + positively upgrade the actions of sirtuins (SIRTs), which are specifically involved in cell survival and metabolic homeostasis ( 171 – 174 ). However, sirtuins are identified to be the NAD + -dependent type III deacetylases that may be collectively activated by increasing their co-substrate NAD + ( 173 ). This knowledge, in line with renalase’s capability to modulate the pool of NAD + , in the experimental setting, provides the proof of principle that renalase may be indirectly implicated in the modulation of sirtuin activities.…”

“…This knowledge, in line with renalase’s capability to modulate the pool of NAD + , in the experimental setting, provides the proof of principle that renalase may be indirectly implicated in the modulation of sirtuin activities. This novel relationship may be of particular interest regarding the scope of this review, since there is ample current evidence that implies sirtuins significance in myocardial fibrotic response, and their cardioprotective effects in experimental settings ( 173 – 195 ). However, this is the first review that scrutinizes renalase’s activity through its relationship with sirtuins.…”

“…Similarly, in the experimental model of cardiac fibrosis, the upregulation of SIRT1 results in TGF-β, and pSMAD3/SMAD3 suppression, followed by significantly reduced fibroblast activation ( 180 ). Furthermore, SIRT1 has the potential to reduce macrophage-based NF-κβ activation ( 183 ), resulting in significant anti-inflammation that slows fibrosis progression, and regulates p53 activity in cardiomyocytes ( 173 ). Sirtuin 1 activation also improves mitochondrial function, reduces oxidative stress and fibrosis, silences proinflammatory pathways ( 184 ), and prevents profibrotic phenotypic alterations in the myocardium by inhibiting NF-κβ and MMP9 transcriptional activation ( 185 ).…”

“…Comparatively, abundant evidence suggests that the downregulation of mitochondrial sirtuin 3 (SIRT3) has a causative role in a number of cardiac pathologies, including the development of cardiac fibrosis and adverse heart remodeling ( 173 , 177 , 178 , 181 , 182 , 188 – 195 ). In particular, SIRT3 deficiency results in exacerbated cardiac hypertrophy and subsequent cardiac fibrosis, whereas cardiac hypertrophy, followed by fibrosis, can be inhibited by the upregulation or activation of SIRT3 ( 188 ), presuming that SIRT3 mitigates cardiac fibroproliferation ( 182 , 188 ).…”