Key result
Metformin and telmisartan mitigate endothelial dysfunction by activating the AMPK-PARP1 cascade to inhibit PARP1 activity.
Why the study?
Do metformin and telmisartan mitigate endothelial dysfunction via AMPK phosphorylation of PARP1 in cultured ECs and rodent models?
Do metformin and telmisartan mitigate endothelial dysfunction via AMPK phosphorylation of PARP1 in cultured ECs and rodent models?
p-value: p=<0.05
Metformin and telmisartan protect vascular endothelium by activating the AMPK-PARP1 cascade, reducing oxidative stress-induced endothelial dysfunction.
Supports AMPK-PARP1 inhibition as endothelial protection mechanism by metformin/telmisartan in models; leaves open clinical translation.
Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction.
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Shang et al. (2016) studied Endothelial dysfunction in hyperglycemia and hypertension. Metformin and Telmisartan vs. Glipizide, Metoprolol, or Vehicle was evaluated on AMPK and PARP1 Ser-177 phosphorylation, and PARP1 activity (p=<0.05). Metformin and telmisartan mitigate endothelial dysfunction by activating the AMPK-PARP1 cascade to inhibit PARP1 activity and protein PARylation in endothelial cells.
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