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PTEN 缺失促进人冠状动脉病理性血管重构。

PTEN deficiency promotes pathological vascular remodeling of human coronary arteries.

机构信息

Division of Cardiology, Department of Medicine.

Division of Renal Diseases and Hypertension, Department of Medicine.

出版信息

JCI Insight. 2018 Feb 22;3(4). doi: 10.1172/jci.insight.97228.

DOI:10.1172/jci.insight.97228
PMID:29467331
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5916252/
Abstract

Phosphatase and tensin homolog (PTEN) is an essential regulator of the differentiated vascular smooth muscle cell (SMC) phenotype. Our goal was to establish that PTEN loss promotes SMC dedifferentiation and pathological vascular remodeling in human atherosclerotic coronary arteries and nonatherosclerotic coronary arteries exposed to continuous-flow left ventricular assist devices (CF-LVADs). Arteries were categorized as nonatherosclerotic hyperplasia (NAH), atherosclerotic hyperplasia (AH), or complex plaque (CP). NAH coronary arteries from CF-LVAD patients were compared to NAH coronaries from non-LVAD patients. Intimal PTEN and SMC contractile protein expression was reduced compared with the media in arteries with NAH, AH, or CP. Compared with NAH, PTEN and SMC contractile protein expression was reduced in the media and intima of arteries with AH and CP. NAH arteries from CF-LVAD patients showed marked vascular remodeling and reduced PTEN and α-smooth muscle actin (αSMA) in medial SMCs compared with arteries from non-LVAD patients; this correlated with increased medial collagen deposition. Mechanistically, compared with ApoE-/- mice, SMC-specific PTEN-null/ApoE-/- double-knockout mice exhibited accelerated atherosclerosis progression and increased vascular fibrosis. By microarray and validated quantitative RT-PCR analysis, SMC PTEN deficiency promotes a global upregulation of proinflammatory and profibrotic genes. We propose that PTEN is an antiinflammatory, antifibrotic target that functions to maintain SMC differentiation. SMC loss of PTEN results in pathological vascular remodeling of human arteries.

摘要

磷酸酶与张力蛋白同源物（PTEN）是血管平滑肌细胞（SMC）分化表型的重要调节因子。我们的目标是确定 PTEN 缺失是否会促进人动脉粥样硬化性冠状动脉和暴露于连续流左心室辅助装置（CF-LVAD）的非动脉粥样硬化性冠状动脉中的 SMC 去分化和病理性血管重构。将动脉分为非动脉粥样硬化性增生（NAH）、动脉粥样硬化性增生（AH）或复合斑块（CP）。与非 LVAD 患者的 NAH 冠状动脉相比，CF-LVAD 患者的 NAH 冠状动脉中的内膜 PTEN 和 SMC 收缩蛋白表达减少。与 NAH 相比，AH 和 CP 中的动脉中，PTEN 和 SMC 收缩蛋白表达在内膜和中膜中减少。与非 LVAD 患者的动脉相比，CF-LVAD 患者的 NAH 动脉显示出明显的血管重构，以及中膜 SMC 中的 PTEN 和α-平滑肌肌动蛋白（αSMA）减少；这与中膜胶原沉积增加有关。在机制上，与 ApoE-/- 小鼠相比，SMC 特异性 PTEN 缺失/ApoE-/- 双敲除小鼠表现出加速的动脉粥样硬化进展和增加的血管纤维化。通过微阵列和验证的定量 RT-PCR 分析，SMC PTEN 缺失促进了促炎和促纤维化基因的整体上调。我们提出，PTEN 是一种抗炎、抗纤维化的靶点，可维持 SMC 分化。SMC 中 PTEN 的缺失导致人动脉的病理性血管重构。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/2ad52f5b14cc/jciinsight-3-97228-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/119a74bf6896/jciinsight-3-97228-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/c6abdf71e8d1/jciinsight-3-97228-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/effab2d0206f/jciinsight-3-97228-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/7d62708d736f/jciinsight-3-97228-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/238b15098c03/jciinsight-3-97228-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/8d1014f72a77/jciinsight-3-97228-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/2162a6377a43/jciinsight-3-97228-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/94b3a21899cb/jciinsight-3-97228-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/2ad52f5b14cc/jciinsight-3-97228-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/119a74bf6896/jciinsight-3-97228-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/c6abdf71e8d1/jciinsight-3-97228-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/effab2d0206f/jciinsight-3-97228-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/7d62708d736f/jciinsight-3-97228-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/238b15098c03/jciinsight-3-97228-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/8d1014f72a77/jciinsight-3-97228-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/2162a6377a43/jciinsight-3-97228-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/94b3a21899cb/jciinsight-3-97228-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5f/5916252/2ad52f5b14cc/jciinsight-3-97228-g009.jpg

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