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      PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice.

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          Abstract

          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.

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          Author and article information

          Journal
          Hypertension
          Hypertension (Dallas, Tex. : 1979)
          Ovid Technologies (Wolters Kluwer Health)
          1524-4563
          0194-911X
          November 2018
          : 72
          : 5
          Affiliations
          [1 ] From the The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China (E.-s.L., F.J., M.-x.Z.).
          [2 ] Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, China (W.-w.B.).
          [3 ] Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China (H.W., J.-n.Z., F.Z., Y.M., X.-m.C., W.-d.Q.).
          [4 ] The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (F.J.).
          [5 ] Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, China (F.J.).
          [6 ] Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, China (M.Y.).
          Article
          10.1161/HYPERTENSIONAHA.118.11184
          30354818

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