Bisphosphonates inhibit ischemia induced neovascularization and attenuate abdominal aortic aneurysm through matrix metalloproteinase inhibition

• Main Authors: Shih-Hung Tsai, 蔡適鴻
• Other Authors: Shing-Jong Lin
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/46489412252652298599

博士 === 國立陽明大學 === 臨床醫學研究所 === 103 === Introduction Bisphosphonates are a class of pharmacologic compounds that are commonly used to treat postmenopausal osteoporosis and malignant osteolytic processes. Nitrogen-containing bisphosphonates (N-BPs) have been shown to exert matrix metalloproteinases (MMPs) inhibition, lipid modifying, anti-atherogenic and anti-angiogenic effects. The potential side effects and repurposing of N-BPs into cardiovascular therapeutics worth further exploring. Studies have shown that bone marrow-derived endothelial progenitor cells (EPCs) play a significant role in postnatal neovascularization. Rupture of abdominal aortic aneurysm (AAA) can be life threatening. Most of AAA have been found incidentally. The pathogenesis of an aortic aneurysm is a failure in the balance of the extracellular matrix degradation and synthesis in the aortic wall. Currently, there was no effective medical treatment to inhibit aneurysm growth or reduce the need for AAA repair. Thus in addition to commonly used cardiovascular risk reducing therapy, an adjunctive medical intervention is still required to change current approach in aneurysm management. In the serial studies, we aimed to know that: 1) whether a potent N-BP, zoledronate had a negative impact on ischemia-induced neovascularization by modulating EPCs functions; and 2) whether zoledronate could have beneficial effects on AngII-induced AAAs in hyperlipidemic mice. Materials and Methods In the first part of the study, unilateral hindlimb ischemia was surgically induced in wild-type mice after 2 weeks of treatment with vehicle or zoledronate (low-dose: 30 μg/kg/week; high-dose: 100 μg/kg/week). Primarily cultured human EPCs were obtained and were used to perform functional assays. In the second part of the study, low-density lipoprotein receptor-/- mice infused for 28 days with AngII were treated with either placebo or zoledronate 100 μg/kg/day. Human aortic endothelial cells and THP-1 cells were used for in vitro experiments. Results In the first part of the study, administration of zoledronate at clinically relevant concentrations diminished blood flow recovery and diminished neovascularization in wild-type mice that had undergone surgically induced hindlimb ischemia. Treatment with zoledronate downregulated VEGF, eNOS, Akt, and MMP-9 activities in ischemic tissues, resulted in reduced numbers EPC-like cells in bone marrow, and inhibited the mobilization of EPCs in response to acute ischemia. The in vitro studies further demonstrated that zoledronate suppressed EPCs viability, EPCs migration, and EPCs tube-forming capacity. In the second part of the study, we showed that administration of zoledronate decreased aortic elastin destruction, reduced MMP-2 activity, and attenuated vascular inflammation by suppression of macrophage infiltration in aortic aneurysmal tissues. In in vitro studies, we showed that zoledronate decreased AngII-promoted vascular inflammation and diminished monocyte adhesion through downregulation of adhesion molecule expression through inactivation of Rho/ROCK dependent JNK and NF-kB activation. Conclusions The findings of zoledronate inhibited ischemia-induced neovascularization by impairing EPCs mobilization and angiogenic functions suggest that administration of zoledronate should be withheld in patients with acute ischemic events to prevent potential anti-angiogenesis effects. Our study further provides for the first time that a therapeutic rationale for the use of zoledronate in the medical treatment of AAA.