Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats
Endothelial dysfunction and hypercontractility of vascular myocytes are ameliorated by fluvastatin in obese Zucker rats
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DOI：
10.1152/ajpheart.00751.2004
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发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Hirata, Y
中科院分区：
文献类型：
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作者：
Nishimatsu, H;Suzuki, E;Hirata, Y
为了研究糖尿病血管功能障碍的机制，我们检测了肥胖Zucker（OZ）、瘦Zucker（LZ）和给予氟伐他汀（OZ + Flu）的OZ大鼠主动脉对肾上腺髓质素（AM）和ANG II的反应。与LZ大鼠相比，OZ大鼠中AM诱导的内皮依赖性血管舒张受损，氟伐他汀恢复了AM诱导的内皮依赖性血管舒张（10（-7）mol/l AM时的%Delta张力; LZ，-85.1 +/- 3.1%; OZ，-50.7 +/- 2.5%; OZ + Flu，-75.6 +/- 2.7%）。在OZ大鼠中，AM（10（-7）mol/l）引起的内皮型一氧化氮合酶（eNOS）表达和Akt磷酸化也减少。氟伐他汀恢复了eNOS表达和Akt磷酸化[eNOS表达（相对强度）：LZ，2.3 +/- 0.4; OZ，1.0 +/- 0.2; OZ + Flu，1.8 +/- 0.3; Akt磷酸化（相对强度）：LZ，2.3 +/- 0.2; OZ，1.0 +/- 0.3; OZ + Flu，1.9 +/- 0.2]。血管紧张素II诱导的血管收缩增强OZ大鼠的主动脉环相比，LZ大鼠，这种增强的血管收缩被氟伐他汀部分正常化，并被取消时，OZ大鼠的主动脉与Rho激酶抑制剂Y-27632预孵育。与LZ大鼠相比，OZ大鼠中GTP γ S诱导的透化主动脉平滑肌细胞收缩增强，这是Rho依赖性Ca 2+致敏收缩的指标，并且这种增强的收缩在OZ + Flu大鼠中受到抑制。这些结果表明，内皮依赖性血管舒张功能受损，Ca 2+的收缩增敏作用在OZ大鼠的血管和氟伐他汀恢复血管功能，激活Akt依赖性途径和抑制Rho依赖性途径。
To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin ( AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Delta tension at 10(-7) mol/l AM; LZ, - 85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, - 75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase ( eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTP gamma S-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca2+ sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca2+ sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.