Boodhwani Munir, Mieno Shigetoshi, Feng Jun, Sodha Neel R, Clements Richard T, Xu Shu-Hua, Sellke Frank W
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA.
J Thorac Cardiovasc Surg. 2008 Jan;135(1):117-22. doi: 10.1016/j.jtcvs.2007.04.021.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, used routinely in patients with coronary disease, can improve endothelial function but can have biphasic and dose-dependent effects on angiogenesis. In vitro evidence suggests that the proangiogenic effects of statins are linked to activation of Akt, a mediator of endothelial cell survival and an activator of endothelial nitric oxide synthase. We investigated the functional and molecular effects of atorvastatin supplementation on microvascular function and the endogenous angiogenic response to chronic myocardial ischemia in normocholesterolemic swine.
Yucatan miniswine were fed a normal diet with (ATOR, n = 7) or without (control, n = 8) atorvastatin (1.5 mg/kg/d) for 20 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Myocardial perfusion was assessed at 3 and 7 weeks using isotope-labeled microspheres. In vitro microvessel relaxation responses and myocardial protein expression were evaluated.
Endothelium-dependent relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were intact in both groups. The ATOR group demonstrated impaired microvessel relaxation to vascular endothelial growth factor (53% +/- 3% vs 70% +/- 7%, ATOR vs NORM at 10(-10) mol/L, P = .05) and fibroblast growth factor-2 (35% +/- 3% vs 57% +/- 5%, ATOR vs NORM at 10(-10) mol/L, P = .04). Baseline-adjusted myocardial perfusion in the ischemic circumflex territory was significantly reduced in the ATOR group (-0.29 +/- 0.10 mL/min/g vs NORM, P = .009). Phosphorylation of Akt was significantly increased in the ATOR group (+235% +/- 72%, P = .009 vs NORM), as was the myocardial expression of endostatin, an antiangiogenic protein (+51% +/- 9%, P < .001 vs NORM). Expression of vascular endothelial growth factor, Tie-2, fibroblast growth factor receptor-1, and endothelial nitric oxide synthase was similar in both groups.
Atorvastatin supplementation is associated with impaired growth factor-mediated microvessel relaxation and a significant reduction in collateral-dependent perfusion. Chronic Akt activation, increased myocardial expression of endostatin, and impaired growth factor signaling may account for the diminished endogenous angiogenic response observed with atorvastatin treatment.
他汀类药物，即3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，常用于冠心病患者，可改善内皮功能，但对血管生成可能具有双相和剂量依赖性作用。体外证据表明，他汀类药物的促血管生成作用与Akt的激活有关，Akt是内皮细胞存活的介质和内皮型一氧化氮合酶的激活剂。我们研究了阿托伐他汀补充剂对正常胆固醇血症猪微血管功能以及慢性心肌缺血内源性血管生成反应的功能和分子影响。
给尤卡坦小型猪喂食含（阿托伐他汀组，n = 7）或不含（对照组，n = 8）阿托伐他汀（1.5 mg/kg/d）的正常饮食，持续20周。通过在左旋支动脉周围放置阿霉素缩窄环诱导慢性缺血。在3周和7周时使用同位素标记的微球评估心肌灌注。评估体外微血管舒张反应和心肌蛋白表达。
两组中对二磷酸腺苷的内皮依赖性舒张和对硝普钠的非内皮依赖性舒张均正常。阿托伐他汀组显示对血管内皮生长因子的微血管舒张受损（10⁻¹⁰ mol/L时，阿托伐他汀组为53%±3%，正常组为70%±7%，P = 0.05）以及对成纤维细胞生长因子-2的微血管舒张受损（10⁻¹⁰ mol/L时，阿托伐他汀组为35%±3%，正常组为57%±5%，P = 0.04）。阿托伐他汀组缺血左旋支区域经基线调整后的心肌灌注显著降低（-0.29±0.10 mL/min/g vs正常组，P = 0.009）。阿托伐他汀组Akt的磷酸化显著增加（+235%±72%，与正常组相比P = 0.009），抗血管生成蛋白内皮抑素的心肌表达也增加（+51%±9%，与正常组相比P < 0.001）。两组中血管内皮生长因子、Tie-2、成纤维细胞生长因子受体-1和内皮型一氧化氮合酶的表达相似。
补充阿托伐他汀与生长因子介导的微血管舒张受损以及侧支循环依赖性灌注显著降低有关。慢性Akt激活以及内皮抑素心肌表达增加和生长因子信号受损可能是阿托伐他汀治疗后观察到的内源性血管生成反应减弱的原因。
