Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Cardiovasc Res. 2010 May 1;86(2):274-82. doi: 10.1093/cvr/cvp425. Epub 2010 Jan 5.
Phosphatase and tensin homolog (PTEN) is implicated as a negative regulator of vascular smooth muscle cell (SMC) proliferation and injury-induced vascular remodelling. We tested if selective depletion of PTEN only in SMC is sufficient to promote SMC phenotypic modulation, cytokine production, and enhanced neointima formation.
Smooth muscle marker expression and induction of pro-inflammatory cytokines were compared in cultured SMC expressing control or PTEN-specific shRNA. Compared with controls, PTEN-deficient SMC exhibited increased phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signalling and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity, reduced expression of SM markers (SM-alpha-actin and calponin), and increased production of stromal cell-derived factor-1alpha (SDF-1alpha), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and chemokine (C-X-C motif) ligand 1 (KC/CXCL1) under basal conditions. PI3K/Akt or mTOR inhibition reversed repression of SM marker expression, whereas PI3K/Akt or NF-kappaB inhibition blocked cytokine induction mediated by PTEN depletion. Carotid ligation in mice with genetic reduction of PTEN specifically in SMC (SMC-specific PTEN heterozygotes) resulted in enhanced neointima formation, increased SMC hyperplasia, reduced SM-alpha-actin and calponin expression, and increased NF-kappaB and cytokine expression compared with wild-types. Lesion formation in SMC-specific heterozygotes was similar to lesion formation in global PTEN heterozygotes, indicating that inactivation of PTEN exclusively in SMC is sufficient to induce considerable increases in neointima formation.
PTEN activation specifically in SMC is a common upstream regulator of multiple downstream events involved in pathological vascular remodelling, including proliferation, de-differentiation, and production of multiple cytokines.
磷酸酶与张力蛋白同源物（PTEN）被认为是血管平滑肌细胞（SMC）增殖和损伤诱导的血管重构的负调控因子。我们检测了仅在 SMC 中选择性耗尽 PTEN 是否足以促进 SMC 表型调节、细胞因子产生和增强的新生内膜形成。
在表达对照或 PTEN 特异性 shRNA 的培养 SMC 中比较了平滑肌标志物表达和促炎细胞因子的诱导。与对照组相比，PTEN 缺陷型 SMC 表现出增加的磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（Akt）/雷帕霉素靶蛋白（mTOR）信号和核因子 kappa 轻链增强子的 B 细胞（NF-κB）活性，减少 SM 标志物（SM-α-肌动蛋白和钙调蛋白）的表达，并增加基质细胞衍生因子-1alpha（SDF-1alpha）、单核细胞趋化蛋白-1（MCP-1）、白细胞介素-6（IL-6）和趋化因子（C-X-C 基序）配体 1（KC/CXCL1）的产生在基础条件下。PI3K/Akt 或 mTOR 抑制逆转了 SM 标志物表达的抑制，而 PI3K/Akt 或 NF-κB 抑制阻断了由 PTEN 耗竭介导的细胞因子诱导。在 SMC 中特异性降低 PTEN 表达的基因敲除小鼠（SMC 特异性 PTEN 杂合子）的颈动脉结扎导致新生内膜形成增强、SMC 过度增生增加、SM-α-肌动蛋白和钙调蛋白表达减少以及 NF-κB 和细胞因子表达增加，与野生型相比。SMC 特异性杂合子中的病变形成与全局 PTEN 杂合子中的病变形成相似，表明仅在 SMC 中失活 PTEN 足以引起新生内膜形成的显著增加。
PTEN 特异性在 SMC 中的激活是涉及病理性血管重构的多个下游事件的共同上游调节剂，包括增殖、去分化和多种细胞因子的产生。
