Intermedin Inhibits DNA Damage-Promoted Senescent Phenotype Transition of Vascular Smooth Muscle Cells in Aorta by Activating NAMPT/PARP1 in Mice

<b>Background and aims</b>: The senescent phenotype transition of vascular smooth muscle cells (VSMCs) is a crucial risk factor for the occurrence and development of vascular diseases. Intermedin (IMD) has various protective effects on cardiovascular diseases. In this study, we aimed to explore the role and the related mechanism of IMD in the senescent phenotype transition of VSMCs of aorta in mice. <b>Methods</b>: The senescent phenotype transition of VSMCs was induced by angiotensin II (Ang II) administered by mini-osmotic pumps in <i>Adm2</i>^fl/fl and <i>Adm2</i>^fl/fl<i>Tag</i>Cre mice. Mouse VSMCs from aorta were used in in vitro experiments. <b>Results</b>: The aortic mRNA level of <i>IMD</i>, namely <i>Adm2,</i> was significantly decreased in Ang II-treated mice. Senescence-associated β-galactosidase activity and protein expressions of p16 and p21 were increased in the aortas of <i>Adm2</i>^fl/fl<i>Tag</i>Cre mice, which were further elevated in Ang II-treated <i>Adm2</i>^fl/fl<i>Tag</i>Cre mice. In addition, <i>Adm2</i> deficiency in VSMCs further increased the protein expressions of DNA damage markers including 53BP1 and γH2AX in aortas of <i>Adm2</i>^fl/fl<i>Tag</i>Cre mice, and Ang II treatment increased their levels in aortas of <i>Adm2</i>^fl/fl<i>Tag</i>Cre mice or in VSMCs. However, Ang II-induced increases in senescence-associated proteins and DNA damage markers could be mitigated by the administration of IMD in vitro. Mechanistically, IMD increased intracellular NAD⁺ by activating nicotinamide phosphoribosyl transferase (NAMPT), followed by enhancing poly (ADP-ribose) polymerase-1 (PARP1) activity. Inhibitors of PARP1 or NAMPT effectively blocked the beneficial role of IMD in the DNA damage of VSMCs. <b>Conclusions</b>: IMD alleviates DNA damage partially by activating NAMPT/PARP1, thereby inhibiting the senescent phenotype transition of VSMCs of aorta, which might shed new light on the prevention of vascular aging.