Nicotinamide N-methyltransferase in cardiovascular Diseases: Mechanistic insights and therapeutic potential

Cardiovascular diseases (CVDs), including conditions like ischemic heart disease, heart failure (HF), and atherosclerosis (AS), have complex pathogenesis that involves both behavioral and metabolic factors. Nicotinamide N-methyltransferase (NNMT) is an enzyme involved in the methylation of nicotinamide (NAM), and its increased activity is associated with disruptions in the NAD⁺ and methionine cycles. These disruptions are considered significant risk factors for cardiovascular diseases, though the specific mechanisms of NNMT remain unclear. This review discusses the role of NNMT in cardiovascular diseases by modulating NAD⁺ and methionine metabolism, including mechanisms such as NAD⁺ depletion, mitochondrial energy crisis, SIRTs deactivation, PARP hyperactivation, as well as hyperhomocysteinemia and epigenetic dysregulation. NNMT is linked to diseases such as atherosclerosis, pulmonary arterial hypertension, heart failure, and coronary heart disease, playing a critical role in their progression. Moreover, the potential of NNMT as a therapeutic target for cardiovascular diseases is explored. RNAi therapies, NNMT small-molecule inhibitors, and exercise therapies are promising treatment approaches, but there are limitations in current research, including discrepancies between animal models and human tissue expression, the dual role of NNMT, and the dose-dependent effects of NNMT inhibitors. Future studies should further clarify NNMT's mechanisms and assess its feasibility as a therapeutic target, aiming to develop more effective treatments and enhance prevention and treatment strategies for cardiovascular diseases.