Targeting on the NAD+‐mitophagy axis to treat cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death worldwide, responsible for over 30% (approximately 18 million) of all deaths in 2016 (World Health Organization). Vascular dysfunction resulting from atherosclerosis, thrombosis or high blood pressure is a common cause of CVD, which compromises organ function.2-4 Ageing and inflammation are the principle drivers of vascular diseases, including the development and clinical manifestations of atherosclerosis. Atherosclerosis is a progressive inflammatory disease characterized by accumulation of cholesterol-laden lipoproteins in the arterial vessel wall.4 The molecular mechanisms underlying atherosclerosis pathogenesis are not fully understood with current therapeutic interventions not satisfactory.


E D I T O R I A L
Targeting on the NAD + -mitophagy axis to treat cardiovascular disease 1

| INTRODUC TI ON
In view of the recent finding of impaired NAD + -mitophagy axis in the cardiovascular disease-predisposed Werner syndrome, 1 we here discuss the application of such discovery in general age-predisposed cardiovascular disease.

| C ARD I OVA SCUL AR D IS E A S E IS A MA JOR BURDEN IN THE ELDERLY
Cardiovascular disease (CVD) is the leading cause of death worldwide, responsible for over 30% (approximately 18 million) of all deaths in 2016 (World Health Organization). Vascular dysfunction resulting from atherosclerosis, thrombosis or high blood pressure is a common cause of CVD, which compromises organ function. [2][3][4] Ageing and inflammation are the principle drivers of vascular diseases, including the development and clinical manifestations of atherosclerosis. Atherosclerosis is a progressive inflammatory disease characterized by accumulation of cholesterol-laden lipoproteins in the arterial vessel wall. 4 The molecular mechanisms underlying atherosclerosis pathogenesis are not fully understood with current therapeutic interventions not satisfactory.

| IMPAIRED NAD + -MITOPHAGY A XIS LINK S TO C ARD I OVA SCUL AR D IS E A S E
Mitochondrial dysfunction plays a major role in atherosclerosis etiology. 4 Mitochondria are considered as the "powerhouses" of cells that play a critical role in developmental and adult neuroplasticity and neuronal survival. 1,5 There is a strong association between increased production of mitochondrial reactive oxygen species (ROS), accumulation of mitochondrial DNA damage, respiratory chain dysfunction and atherosclerosis. 3,4 Thus, efficient cellular clearance of damaged mitochondria through mitochondrial specific autophagy, termed mi- The mitophagy inducer NAD + is a fundamental molecule necessary for all living organism. 5 NAD + levels decline in an age-dependent manner. 1,5 It is a necessary cofactor for many key metabolic pathways, including glycolysis, tricarboxylic acid (TCA) cycle, fatty acid β-oxidation, and mitochondrial oxidative phosphorylation (OXPHOS). 5 Furthermore, NAD + is also a coenzyme for at least three groups of proteins, including cyclic ADP-ribose synthases, poly(ADP-ribose) polymerases (PARPs), and deacetylases from the sirtuin family (SIRTs). 5 With the growing interest in NAD + in healthy ageing, it seems that NAD + affects broad organ systems and modulates an expanding list of disease processes. We recently proposed that the NAD + -mitophagy axis plays a fundamental role in maintaining healthy ageing and neuroprotection. 5 Moreover, a recent study shows that NAD + boosting inhibits age-dependent endothelial dysfunction, leading to improvement of neovascularization, blood flow, and increased mobility and endurance of aged mice. 7 The integrin-YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif)-JNK (c-Jun N-terminal kinase) cascade is a newly discovered pathway which mediates atheroprotective effects of unidirectional shear flow. 2 Based on current literature and our unpublished data, we propose an age-dependent impairment of mitophagy causes endothelial dysfunction, metabolic imbalance, inflammation, as well as senescence, collectively contributing to atherosclerosis; accordingly, targeting on the NAD + -mitophagy pathway may provide a therapeutic strategy for CVD, including the reduction of the occurrence of atherosclerosis ( Figure 1).

| CON CLUS I ON S AND FUTURE PER S PEC TIVE S
NAD + maintains a broad metabolic homeostasis and protects against age-dependent endothelial dysfunction and may provide novel preventive/therapeutic strategies in pathological and normal vascular ageing-associated atherosclerosis. Further animal and clinical studies to verify such NAD + -dependent benefits are necessary.