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PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice.
Hypertension. 2018 11; 72(5):1189-1199.H

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.

Authors+Show Affiliations

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.).Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, China (W.-w.B.).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.).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.).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.).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.).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.). The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China (F.J.). Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, China (F.J.).Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, China (M.Y.).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.).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.).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.).

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30354818

Citation

Liang, Er-Shun, et al. "PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice." Hypertension (Dallas, Tex. : 1979), vol. 72, no. 5, 2018, pp. 1189-1199.
Liang ES, Bai WW, Wang H, et al. PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice. Hypertension. 2018;72(5):1189-1199.
Liang, E. S., Bai, W. W., Wang, H., Zhang, J. N., Zhang, F., Ma, Y., Jiang, F., Yin, M., Zhang, M. X., Chen, X. M., & Qin, W. D. (2018). PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice. Hypertension (Dallas, Tex. : 1979), 72(5), 1189-1199. https://doi.org/10.1161/HYPERTENSIONAHA.118.11184
Liang ES, et al. PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice. Hypertension. 2018;72(5):1189-1199. PubMed PMID: 30354818.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PARP-1 (Poly[ADP-Ribose] Polymerase 1) Inhibition Protects From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysm in Mice. AU - Liang,Er-Shun, AU - Bai,Wen-Wu, AU - Wang,Hao, AU - Zhang,Jian-Ning, AU - Zhang,Fan, AU - Ma,Yang, AU - Jiang,Fan, AU - Yin,Mei, AU - Zhang,Ming-Xiang, AU - Chen,Xiao-Mei, AU - Qin,Wei-Dong, PY - 2018/10/26/entrez PY - 2018/10/26/pubmed PY - 2019/5/14/medline KW - angiotensin II KW - aortic aneurysm KW - endothelial cells KW - matrix metalloproteinases KW - oxidative stress SP - 1189 EP - 1199 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 72 IS - 5 N2 - 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. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/30354818/PARP_1__Poly[ADP_Ribose]_Polymerase_1__Inhibition_Protects_From_Ang_II__Angiotensin_II__Induced_Abdominal_Aortic_Aneurysm_in_Mice_ L2 - https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.118.11184?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -