NNMT Safeguards Vascular Aging by Modulating an Endothelial LMNA-HSP Stress-Response Axis.

NNMT expression is inversely associated with older, plaque-adjacent human carotid intimal status, and restoring NNMT in aged mice improves vasodilation and arterial stiffness.

• Why it matters: Vascular endothelial aging contributes to stiffness and impaired dilation, but NNMT’s endothelial role and its linked stress-response mechanism remain unclear.
• What they did: The study compared NNMT across older vs younger plaque-adjacent human donors, primary mouse aortic endothelial cells, and senescent human umbilical vein endothelial cells, then used endothelial-targeted AAV-Tie to restore or knock down NNMT in aged mice. Multiomics and transcriptomic analyses linked NNMT to reduced histone H3 lysine 27 trimethylation at the LMNA promoter, with S-adenosylmethionine effects, and to HSF1 activation and HSP90/HSP70 promoter binding.
• The result: NNMT restoration improved vasodilation and arterial stiffness, while knockdown worsened deficits; Heterophyllin B’s vascular protection was partially attenuated by endothelial NNMT knockdown in vivo.

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