Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade
| Autor: | Jiao Zhang, Zhen Chen, Youyi Zhang, Ting Lei, Han Xiao, Fenqing Shang, Traci L. Marin, Brendan Gongol, Zhao Li, Jin Zhang, Yanjun Yin, John Y.-J. Shyy, Yaqiong Wang |
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| Přispěvatelé: | Huang, Yu |
| Rok vydání: | 2016 |
| Předmět: |
Male
Poly (ADP-Ribose) Polymerase-1 Blood Pressure AMP-Activated Protein Kinases Cardiovascular Biochemistry Vascular Medicine Mice 0302 clinical medicine Endocrinology AMP-activated protein kinase Rats Inbred SHR lcsh:Science Cells Cultured Cultured Organic Compounds Metformin 3. Good health 5.1 Pharmaceuticals Physical Sciences Phosphorylation Poly(ADP-ribose) Polymerases Development of treatments and therapeutic interventions Western Metoprolol medicine.medical_specialty Inbred SHR Cardiotonic Agents Endothelium Endocrine Disorders MAP Kinase Signaling System Cells Knockout Blotting Western Carbohydrates Nitric Oxide 03 medical and health sciences Diabetes Mellitus Humans Protein kinase A Pharmacology lcsh:R Chemical Compounds Biology and Life Sciences Proteins medicine.disease Mice Inbred C57BL 030104 developmental biology Glucose Hyperglycemia Blood Vessels lcsh:Q Benzimidazoles Endothelium Vascular 0301 basic medicine lcsh:Medicine 030204 cardiovascular system & hematology Inbred C57BL Rats Inbred WKY Benzoates Medicine and Health Sciences Telmisartan Endothelial dysfunction Post-Translational Modification Aorta Mice Knockout Multidisciplinary biology Blotting Monosaccharides Diabetes Drugs Chemistry medicine.anatomical_structure Antihypertensive Drugs Hypertension Anatomy medicine.drug Research Article General Science & Technology Real-Time Polymerase Chain Reaction Internal medicine Vascular medicine Animals Inbred WKY Organic Chemistry AMPK Cell Biology Rats Oxidative Stress Metabolic Disorders biology.protein Cardiovascular Anatomy Glipizide |
| Zdroj: | PloS one, vol 11, iss 3 PLoS ONE PLoS ONE, Vol 11, Iss 3, p e0151845 (2016) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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