Nicotinamide Mononucleotide (NMN) Improves the Senescence of Mouse Vascular Smooth Muscle Cells Induced by Ang II Through Activating p-AMPK/KLF4 Pathway

Background: Vascular smooth muscle cells (VSMCs) senescence exacerbates vascular diseases like atherosclerosis and hypertension. Angiotensin II (Ang II) is a strong inducer of VSMCs senescence, causing vascular damage, though its exact mechanism is unclear. Nicotinamide mononucleotide (NMN), a NAD⁺ precursor, has gained attention for its anti-senescence potential, yet its role in inhibiting VSMCs senescence is not fully understood. Methods: This study assessed senescence markers, including β-galactosidase activity (SA-β-gal) and the senescence-associated secretory phenotype (SASP), in mouse VSMCs treated with Ang II alone or with NMN and relevant activators/inhibitors. Results: Compared to controls, SA-β-gal levels and SASP secretion significantly increased in Ang II-exposed cells. In contrast, NMN reduced the expression of both markers. NMN also reversed Ang II-induced VSMCs senescence by downregulating KLF4 and p16 through AMPK activation, which Ang II inhibited, while decreasing mRNA levels of key SASP components. The effects of the AMPK Activator AICAR were similar to those of NMN, whereas the AMPK Inhibitor Compound C negated NMN's effects. Conclusions: In summary, NMN mitigates Ang II-induced mouse VSMCs senescence via the AMPK/KLF4/p16 pathway. This study underscores the anti-senescence effects of NMN on mouse VSMCs, supporting further exploration of its potential as a food supplement for preventing and treating vascular senescence.

AMPK/KLF4/p16 pathway; Angiotensin II; nicotinamide mononucleotide; senescence; vascular smooth muscle cells.