O6-methylguanine-DNA methyltransferase inhibition leads to cellular senescence and vascular smooth muscle dysfunction

Area of Science:

• Cellular senescence
• Vascular biology
• Pharmacology

Background:

• Inhibiting O6-methylguanine-DNA methyltransferase (MGMT) is key to overcoming chemoresistance but is limited by myelosuppression.
• Adverse effects of MGMT inhibitors beyond bone marrow are not well-studied.
• Chemotherapy can induce senescence in healthy tissues, including cardiovascular damage.

Purpose of the Study:

• To investigate the impact of the MGMT inhibitor O6-benzylguanine (BG) on aortic vascular smooth muscle cells (VSMCs) and aorta.
• To characterize BG-induced senescence in VSMCs and its functional consequences on vascular reactivity.

Main Methods:

• VSMCs and rat aorta were treated with BG.
• Cellular senescence was assessed by morphology, SAβGal activity, and senescence markers (p27, γH2A.X).
• Signaling pathways (Erk1/2, p38α, Akt, mTORC1) and cell cycle regulators were analyzed.
• Vascular reactivity of aortic rings and in vivo responses in rats were measured.

Main Results:

• BG induced VSMC senescence, characterized by altered morphology, reduced growth, increased SAβGal activity, and elevated p27 and γH2A.X.
• BG activated senescence-related pathways and induced cell cycle arrest at G2/M via pCDK1.
• BG impaired vascular reactivity in aortic rings and in rats, specifically reducing the response to sodium nitrite.

Conclusions:

• O6-benzylguanine (BG) induces senescence in vascular smooth muscle cells and impairs vascular reactivity.
• These findings highlight potential adverse cardiovascular effects of MGMT inhibitors.
• Caution is warranted in the clinical use of MGMT inhibitors due to potential vascular toxicity.