PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice
| Autor: | Fan Zhang, Ming-Xiang Zhang, Yang Ma, Weidong Qin, Jian-ning Zhang, Wen-wu Bai, Er-shun Liang, Fan Jiang, Mei Yin, Xiaomei Chen, Hao Wang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Poly ADP ribose polymerase Myocytes Smooth Muscle Poly (ADP-Ribose) Polymerase-1 Blood Pressure 030204 cardiovascular system & hematology Article 03 medical and health sciences Mice 0302 clinical medicine Internal medicine Internal Medicine medicine Animals RNA Small Interfering Protein kinase B Mice Knockout Chemistry Kinase Angiotensin II NF-kappa B Endothelial Cells Cell migration Intercellular Adhesion Molecule-1 Oxidative Stress 030104 developmental biology Endocrinology Apoptosis cardiovascular system Cytokines Tumor necrosis factor alpha Collagen Signal transduction Aortic Aneurysm Abdominal DNA Damage Signal Transduction |
| Zdroj: | Hypertension (Dallas, Tex. : 1979). 72(5) |
| ISSN: | 1524-4563 |
| Popis: | Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. PARP-1 (poly[ADP-ribose] polymerase 1) is a nuclear enzyme, which plays a critical role in vascular diseases. We hypothesized that PARP-1 inhibition might have protective effects on AAA. In vivo, Ang II (angiotensin II) was continuously infused by a micropump for 28 days to induce AAA in mice. In vitro, aortic endothelial cells and smooth muscle cells were stimulated by Ang II for 24 hours. Ang II infusion increased PARP-1 expression and activity and successfully induced AAA formation partly with a hemorrhage in ApoE −/− mice. Genetic deletion of PARP-1 markedly reduced the AAA incidence, abdominal aortic diameter, macrophage infiltration, ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular adhesion molecule 1) expression, and MMP (matrix metalloproteinase) expression, as well as MMP activity; but increased smooth muscle cells content and collagens expression in AAA. PARP-1 inhibition by PJ-34 also exerted a protective effect on AAA in mice. In aortic endothelial cells, Ang II–induced oxidative stress and DNA damage, resulting in increased PARP-1 expression and activity. Compared with the control, Ang II increased TNF-α (tumor necrosis factor α) and IL-6 (interleukin-6) secretions, ICAM-1 expression and THP-1 (human acute monocytic leukemia cell line) cells adhesion, while PARP-1 inhibition by siRNA reduced the inflammatory response probably through inhibition of the phosphorylation of ERK (extracellular signal-regulated kinase), NF-κB (nuclear factor-κB), and Akt signaling pathways. In smooth muscle cells, Ang II promoted cell migration, proliferation, and apoptosis, reduced collagens expression, but increased MMPs expression, while PARP-1 deletion alleviated these effects partly by reducing NF-κB-targeted MMP-9 expression. PARP-1 inhibition might be a feasible strategy for the treatment of AAA. |
| Databáze: | OpenAIRE |
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