Lin Zhong-Wei, Wang Zhuo, Zhu Gui-Ping, Li Bo-Wei, Xie Wen-Lin, Xiang Ding-Cheng
Graduate School of Southern Medical University Guangzhou, China ; Department of Cardiology, The First Affiliated Hospital of Guangdong Pharmaceutical University Guangzhou, China.
Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University Guangzhou, China.
Int J Clin Exp Med. 2015 Feb 15;8(2):2118-27. eCollection 2015.
Fibulin-3, an extracellular glycoprotein, has been suggested as having functions in vessels. In hypertension, extracellular matrix, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play important roles in cardiovascular remodeling. However, the role of Fibulin-3 as an extracellular glycoprotein in hypertensive vascular remodeling remains unclear. Our study was to determine whether Fibulin-3 and TIMPs/MMPs would affect vascular structure during hypertension and the treatment of Xuezhikang. Thirty spontaneously hypertensive rats (SHRs) aged 8 weeks were randomized to three groups: SHRs control group (SHRs group, n=10), group treated with low dose Xuezhikang (XZK-L, 20 mg/kg/d, n=10) and group treated with high dose Xuezhikang (XZK-H, 200 mg/kg/d, n=10), the normal group was comprised of ten Wistar-Kyoto (WKY) rats of the same age. We showed that serum nitric oxide (NO) in control group was significantly lower than WKY group (P<0.05). Concomitantly, serum oxidized low-density lipoprotein (ox-LDL) was higher than WKY group (P<0.05). The treatment of high dose Xuezhikang significantly dicreased ox-LDL, left ventricular mass index (LVMI) and Wall-to-lumen area ratio (W/L) of thoracic aorta (P<0.05), while serum NO was significantly increasing (P<0.05). Moreover, the expressions of Fibulin-3 and MMP-2, 9 at both protein and mRNA levels were significantly higher in thoracic aorta of SHRs group compared to WKY group by immunohistochemistry and western blotting (P<0.05). However, the levels of Fibulin-3 and MMP-2, 9 were significantly decreased in XZK-H group compared to control group (P<0.05). The level of TIMP-3 had no significance difference between SHRs and WKY groups (P>0.05). So the levels of Fibulin-3 and MMP-2, 9 in SHRs could be inhibited by Xuezhikang. Furthermore, a strong correlation in transcript expression was established between Fibulin-3, and MMP-2 (r=0.81, P<0.05) and MMP-9 (r=0.92, P<0.05) through immunohistochemistry. In summary, the overexpression of Fibulin-3 and MMP-2, 9 levels were associated with hypertension and vascular remodeling and inhibited by Xuezhikang. Fibulin-3 is a candidate in the pathogenesis of cardiovascular remodeling in hypertension.
纤连蛋白-3是一种细胞外糖蛋白，有人认为它在血管中发挥作用。在高血压中，细胞外基质、基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制剂（TIMPs）在心血管重塑中起重要作用。然而，纤连蛋白-3作为一种细胞外糖蛋白在高血压血管重塑中的作用仍不清楚。我们的研究旨在确定纤连蛋白-3和TIMPs/MMPs在高血压及血脂康治疗过程中是否会影响血管结构。将30只8周龄的自发性高血压大鼠（SHRs）随机分为三组：SHRs对照组（SHRs组，n = 10）、低剂量血脂康治疗组（XZK-L，20 mg/kg/d，n = 10）和高剂量血脂康治疗组（XZK-H，200 mg/kg/d，n = 10），正常组由10只同龄的Wistar-Kyoto（WKY）大鼠组成。我们发现对照组血清一氧化氮（NO）显著低于WKY组（P<0.05）。同时，血清氧化型低密度脂蛋白（ox-LDL）高于WKY组（P<0.05）。高剂量血脂康治疗显著降低了ox-LDL、左心室质量指数（LVMI）和胸主动脉壁腔面积比（W/L）（P<0.05），而血清NO显著升高（P<0.05）。此外，通过免疫组织化学和蛋白质印迹法检测发现，与WKY组相比，SHRs组胸主动脉中纤连蛋白-3以及MMP-2、9的蛋白和mRNA水平均显著升高（P<0.05）。然而，与对照组相比，XZK-H组中纤连蛋白-3以及MMP-2、9的水平显著降低（P<0.05）。SHRs组和WKY组之间TIMP-3水平无显著差异（P>0.05）。因此，血脂康可抑制SHRs中纤连蛋白-3以及MMP-2、9的水平。此外，通过免疫组织化学发现纤连蛋白-3与MMP-2（r = 0.81，P<0.05）和MMP-9（r = 0.92，P<0.05）的转录表达之间存在强相关性。总之，纤连蛋白-3以及MMP-2、9水平的过表达与高血压和血管重塑相关，并被血脂康抑制。纤连蛋白-3是高血压心血管重塑发病机制中的一个候选因素。
