Both gain and loss of Nampt function promote pressure overload-induced heart failure

The heart requires high-energy production, but metabolic ability declines in the failing heart. Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) synthesis. NAD is directly involved in various metabolic processes and may indirectly regulate metabolic gene expression through sirtuin 1 (Sirt1), an NAD-dependent protein deacetylase. However. how Nampt regulates cardiac function and metabolism in the failing heart is poorly understood. Here we show that pressure-overload (PO)induced heart failure is exacerbated in both systemic Nampt heterozygous knockout (Nampt(+/-)) mice and mice with cardiac-specific Nampt overexpression (Tg-Nampt). The NAD level declined in Nampt(+/-) mice under PO (wild: 377 pmo(/mg tissue; Nampt(+/-): 119 pmol/mg tissue; P = 0.028). In cultured cardiomyocytes, Nampt knockdown diminished mitochondria( NAD content and ATP production (relative ATP production: wild: 1; Nampt knockdown: 0.56; P = 0.0068), suggesting that downregulation of Nampt induces mitochondrial dysfunction. On the other hand, the NAD level was increased in Tg-Nampt mice at baseline but not during PO, possibly due to increased consumption of NAD by Sirt1. The expression of Sirt1 was increased in Tg-Nampt mice, in association with reduced overall protein acetylation. PO-induced downregulation of metabolic genes was exacerbated in Tg-Nampt mice. In cultured cardiomyocytes, Nampt and Sirt1 cooperatively suppressed mitochondrial proteins and ATP production, thereby promoting mitochondrial dysfunction. In addition, Nampt overexpression upregulated inflammatory cytokines. including TNF-alpha and monocyte chemoattractant protein-1. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, whereas Nampt overexpression is detrimental during PO. possibly due to excessive activation of Sirt1, suppression of mitochondrial function, and upregulation of proinflammatory mechanisms. NEW & NOTEWORTHY Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide synthesis. We demonstrate that pressure overload-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout mice and mice with cardiac-specific Nampt overexpression. Both loss- and gain-of-function models exhibited reduced protein acetylation. suppression of metabolic genes, and mitochondrial energetic dysfunction. Thus endogenous Nampt maintains cardiac function and metabolism in the failing heart, but cardiac-specific Nampt overexpression is detrimental rather than therapeutic.