Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine.
Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine.
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DOI：
10.1093/cvr/cvp038
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发表时间：
2009-04
影响因子：
10.8
通讯作者：
D. Tharp;I. Masseau;Jan R. Ivey;V. Ganjam;D. Bowles
中科院分区：
文献类型：
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作者：
D. Tharp;I. Masseau;Jan R. Ivey;V. Ganjam;D. Bowles
本实验室的前期研究表明，睾酮在体内和体外均能增加冠状动脉平滑肌蛋白激酶C δ（PKC δ），并通过PKC δ依赖性方式诱导G（0）/G（1）细胞周期阻滞来抑制冠状动脉平滑肌增殖。本研究的目的是确定内源性睾酮是否限制血管成形术后再狭窄的猪模型中冠状动脉新生内膜（NI）的形成。方法和结果：性成熟的雄性尤卡坦小型猪被保持完整（IM）、去势（CM）或去势后用睾酮替代（CMT; Androgel，10 mg/天）。在左前降支和左回旋支冠状动脉中进行血管成形术，球囊导管过度充盈以诱导中度（1.25-1.3 x直径; 3 x 30 s）或重度（1.4 x直径; 3 x 30 s）损伤，并允许动物恢复10或28天。将损伤的冠状动脉切片切开、固定、染色（Verheoff-Van Gieson，Ki 67，PKC δ，p27）并分析。排除无内弹力层破裂的血管。中度损伤后，与IM和CMT相比，CM的内膜面积、内膜-中膜比率（I/M）和标准化为破裂指数（RI）的I/M增加。RI、中膜面积和内膜/中膜厚度（IMT）在组间无差异。NI形成与血清睾酮浓度呈负相关。相反，在严重损伤后，两组之间没有显著差异。在NI形成期间（损伤后10天），替吉奥抑制增殖并刺激PKC δ和p27（kip 1）表达。结论内源性睾酮抑制了冠状动脉NI的形成，为睾酮在冠状动脉血管增生性疾病如再狭窄和动脉粥样硬化中的保护作用提供了依据。
AIMS Previous studies from our laboratory have demonstrated that testosterone increases coronary smooth muscle protein kinase C delta (PKC delta) both in vivo and in vitro and inhibits coronary smooth muscle proliferation by inducing G(0)/G(1) cell cycle arrest in a PKC delta-dependent manner. The purpose of the present study was to determine whether endogenous testosterone limits coronary neointima (NI) formation in a porcine model of post-angioplasty restenosis. METHODS AND RESULTS Sexually mature, male Yucatan miniature swine were either left intact (IM), castrated (CM), or castrated with testosterone replacement (CMT; Androgel, 10 mg/day). Angioplasty was performed in both the left anterior descending and left circumflex coronary arteries with balloon catheter overinflation to induce either moderate (1.25-1.3 x diameter; 3 x 30 s) or severe (1.4x diameter; 3 x 30 s) injury, and animals were allowed to recover for either 10 or 28 days. Injured coronary sections were dissected, fixed, stained (Verheoff-Van Gieson, Ki67, PKC delta, p27), and analysed. Vessels without internal elastic laminal rupture were excluded. Following moderate injury, intimal area, intima-to-media ratio (I/M), and I/M normalized to rupture index (RI) were increased in CM compared with IM and CMT. RI, medial area, and intimal/medial thickness (IMT) were not different between groups. NI formation was inversely related to serum testosterone concentration. Conversely, following severe injury, there were no significant differences between the groups. Testosterone inhibited proliferation and stimulated PKC delta and p27(kip1) expression during NI formation (10 days post-injury). CONCLUSION These findings demonstrate that endogenous testosterone limits coronary NI formation in male swine and provides support for a protective role for testosterone in coronary vasculoproliferative diseases, such as restenosis and atherosclerosis.