PPARβ/δ, a Novel Regulator for Vascular Smooth Muscle Cells Phenotypic Modulation and Vascular Remodeling after Subarachnoid Hemorrhage in Rats.
PPARβ/δ, a Novel Regulator for Vascular Smooth Muscle Cells Phenotypic Modulation and Vascular Remodeling after Subarachnoid Hemorrhage in Rats.
复制标题
PPAR beta/delta，一种新型调节剂，用于大鼠蛛网膜下腔出血后血管平滑肌细胞表型调节和血管重塑
DOI：
10.1038/srep45234
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发表时间：
2017-03-22
影响因子：
4.6
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Zhang H;Jiang L;Guo Z;Zhong J;Wu J;He J;Liu H;He Z;Wu H;Cheng C;Sun X
脑血管平滑肌细胞（VSMC）表型转换参与了蛛网膜下腔出血（aSAH）后血管损伤的病理生理学，而其分子机制仍在很大程度上是推测。过氧化物酶体增殖物激活受体β/δ（Peroxisome proliferator-activated receptor β/δ，PPARβ/δ）参与调节血管细胞的增殖和血管内环境的稳定。在本研究中，我们研究了PPARβ/δ在SAH后VSMC表型转换中的潜在作用。GW 0742和腺病毒激活的PPAR β/δ（Ad-PPARβ/δ）可显著抑制血红蛋白诱导的VSMC表型转换。然而，磷脂酰肌醇-3激酶-AKT（PI 3 K/AKT）抑制剂LY 294002可部分阻断PPARβ/δ对VSMC表型转换的作用。进一步研究表明，PPARβ/δ诱导的PI 3 K/AKT活化也可促进血清反应因子（SRF）的核定位和Myocardin的表达，与VSMC表型转换密切相关。Ad-PPARβ/δ对SAH大鼠基底动脉内径和血管壁厚度的改变具有正性调节作用。此外，通过腺病毒过表达PPARβ/δ可显著改善神经功能结局。总之，本研究确定了PPARβ/δ作为SAH后VSMC表型转换和血管重塑的有用调节剂，为迟发性脑缺血的治疗策略提供了新的见解。
Cerebral vascular smooth muscle cell (VSMC) phenotypic switch is involved in the pathophysiology of vascular injury after aneurysmal subarachnoid hemorrhage (aSAH), whereas the molecular mechanism underlying it remains largely speculative. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) has been implicated to modulate the vascular cells proliferation and vascular homeostasis. In the present study, we investigated the potential role of PPARβ/δ in VSMC phenotypic switch following SAH. Activation of PPARβ/δ by GW0742 and adenoviruses PPARβ/δ (Ad-PPARβ/δ) significantly inhibited hemoglobin-induced VSMC phenotypic switch. However, the effects of PPARβ/δ on VSMC phenotypic switch were partly obstacled in the presence of LY294002, a potent inhibitor of Phosphatidyl-Inositol-3 Kinase-AKT (PI3K/AKT). Furthermore, following study demonstrated that PPARβ/δ-induced PI3K/AKT activation can also contribute to Serum Response Factor (SRF) nucleus localization and Myocardin expression, which was highly associated with VSMC phenotypic switch. Finally, we found that Ad-PPARβ/δ positively modulated vascular remodeling in SAH rats, i.e. the diameter of basilar artery and the thickness of vessel wall. In addition, overexpression of PPARβ/δ by adenoviruses significantly improved neurological outcome. Taken together, this study identified PPARβ/δ as a useful regulator for VSMC phenotypic switch and vascular remodeling following SAH, providing novel insights into the therapeutic strategies of delayed cerebral ischemia.