Zoledronate attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of Rho/ROCK-dependent JNK and NF-κB pathway.
OBJECTIVE
Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over the age of 65. Nitrogen-containing bisphosphonates (N-BPs) have been shown to exert anti-atherogenic and anti-angiogenic effects, but the potential effects of N-BPs on AAA remain unclear. Here, we tested whether a potent N-BP, zoledronate, can attenuate the formation of Angiotensin II (Ang II)-induced AAA in hyperlipidaemic mice.


RESULTS
Low-density lipoprotein receptor(-/-) (LDLR(-/-)) mice infused for 28 days with Ang II were treated with placebo and 100 μg/kg/day zoledronate. Continuous Ang II infusion in LDLR(-/-) mice exhibited a 59% incidence of AAA formation, and treatment with zoledronate decreased AAA formation (21%). Compared with the saline group, administration of zoledronate in Ang II-infused LDLR(-/-) mice attenuated the expansion of the suprarenal aorta (maximal aortic diameter), reduced elastin degradation in the media layer of the aorta, and significantly diminished vascular inflammation by reduction in vascular cell adhesion molecule expression and macrophage accumulation. Treatment with zoledronate decreased matrix metalloproteinase-2 (MMP-2) in aortic tissues. Zoledronate-treated mice had significant down-regulation of JNK, NF-κB, and reduced Ang II-induced Rho/ROCK activation. Zoledronate reduced monocytes adherence to human aortic endothelial cells in vitro.


CONCLUSIONS
Zoledronate-attenuated Ang II induced AAA formation by suppression of MMP-2 activity and suppressed vascular inflammation and Ang II-induced Rho/ROCK activities.
Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Shih-Hung
SH
Tsai
Po-Hsun
PH
Huang
Yi-Jen
YJ
Peng
Wei-Chou
WC
Chang
Hsiao-Ya
HY
Tsai
Hsin-Bang
HB
Leu
Jaw-Wen
JW
Chen
Shing-Jong
SJ
Lin
D000804:Angiotensin II; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D018920:Coculture Techniques; D004108:Dilatation, Pathologic; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004549:Elastin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000077211:Zoledronic Acid; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004164:Diphosphonates; D007093:Imidazoles; D016328:NF-kappa B; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; C066737:RHOA protein, human; D000077211:Zoledronic Acid; D004549:Elastin; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
Abdominal aortic aneurysm; Angiotensin II; Bisphopsphonate; Low-density lipoprotein receptor-/- mice; MAPK; NF-kB; Rho; Zoledronate