Abstract
High levels of free fatty acids (FFA) are closely associated with obesity and the development of cardiovascular diseases. Recently, nicotinamide adenine dinucleotide (NAD) metabolism has emerged as a potential target for several modern diseases including diabetes. Herein, we explored the underlying mechanisms of NAD metabolism associated with the risk of cardiovascular disease. Our study found that nicotinamide N-methyltransferase (NNMT) mRNA levels were significantly increased in the hearts of FFA-bound-albumin-overloaded mice and in H9C2 cells treated with palmitic acid (PA). We studied the mechanisms underlining the anti-inflammatory and anti-oxidant activities of 1-methylnicotinamide (1-MNA), a metabolite of NNMT. We found a significantly higher level of reactive oxygen species, inflammation, apoptosis, and cell hypertrophy in PA-treated H9C2 cells and this effect was inhibited by 1-MNA treatment. in vivo, 1-MNA improved inflammation, apoptosis, and fibrosis damage in mice and this inhibition was associated with inhibited NF-κB activity. In conclusion, our study revealed that 1-MNA may prevent high fatty diet and PA-induced heart injury by regulating Nrf2 and NF-κB pathways.
Highlights
Elevated plasma free fatty acid (FFA) levels have emerged as a major link between obesity, metabolic syndrome and cardiovascular diseases
We measured the expression of Nrf2-dependent antioxidant defense genes including heme oxygenase1 (HO-1), GCLC, and NADPH quinineoxidoreductase-1 (NQO-1). mRNA (Figure 1C) and protein expression (Figure 1D) of HO-1 and NQO-1 increased significantly after 1-MNA treatment, which similar to that observed for Nrf2
These results indicated that 1-MNA may act as an antioxidant by upregulating Nrf2 and antioxidant-related genes
Summary
Elevated plasma free fatty acid (FFA) levels have emerged as a major link between obesity, metabolic syndrome and cardiovascular diseases. Circulating free fatty acids (FFA), mainly originating from lipolysis in the adipose tissue, has been recognized as one of the most important factors causing systemic organ damage to the heart, liver, and skeletal muscle. These adverse effects are defined lipotoxicity [1]. Increased levels of FFA promote the expression of pro-inflammatory mediators, such as TNF-α, IL-1, and IL-6. These pro-inflammatory factors further induce oxidative stress.
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