Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada, V6T 1Z3.
Cardiovasc Res. 2010 Jul 1;87(1):177-86. doi: 10.1093/cvr/cvq030. Epub 2010 Jan 28.
The presence of metabolic abnormalities such as insulin resistance and elevated levels of various vasoconstrictor G-protein-coupled receptor (GPCR) agonists contributes to the development of hypertension. Recent studies have suggested a link between disease progression and activation of growth factor receptor signalling pathways such as the epidermal growth factor receptor (EGFR) by matrix metalloproteinases (MMPs). We hypothesized that excessive stimulation of GPCRs such as alpha(1)-adrenergic receptors activates MMP-dependent EGFR transactivation and contributes to the development of hypertension by promoting increased synthesis of contractile proteins in vascular smooth muscle (VSM).
We tested this concept in experiments using insulin-resistant VSM cells (VSMCs) and fructose hypertensive rats (FHRs), a model of acquired systolic hypertension and insulin resistance. We found that insulin resistance and agonist stimulation increased the expression and activity of MMPs (MMP-2 and MMP-7), the EGFR, contractile proteins such as myosin light chain kinase and MLC II, and their transcriptional activators including P90 ribosomal kinase (P90RSK) and serum response factor, possibly via the activation of extracellular signal-regulated kinase (ERK1/2) in VSMCs. Further, in insulin-resistant VSMCs and arteries from FHRs, disruption of MMP-EGFR signalling either by a pharmacological or small interfering RNA approach normalized the increased expression and activity of contractile proteins and their transcriptional activators and prevented the development of hypertension in FHRs.
Our data suggest that the MMP-EGFR pathway could be a potential target in the treatment of hypertension in insulin resistance and/or hyperglycaemic conditions such as type 2 diabetes.
代谢异常的存在，如胰岛素抵抗和各种血管收缩 G 蛋白偶联受体（GPCR）激动剂水平升高，是高血压发展的原因。最近的研究表明，疾病进展与生长因子受体信号通路的激活之间存在联系，例如表皮生长因子受体（EGFR）通过基质金属蛋白酶（MMPs）。我们假设，α 1-肾上腺素能受体等 GPCR 的过度刺激会激活 MMP 依赖性 EGFR 反式激活，并通过促进血管平滑肌（VSM）中收缩蛋白的合成来促进高血压的发展。
我们使用胰岛素抵抗的血管平滑肌细胞（VSMCs）和果糖高血压大鼠（FHRs）进行了实验来检验这一概念，FHRs 是获得性收缩期高血压和胰岛素抵抗的模型。我们发现，胰岛素抵抗和激动剂刺激增加了 MMPs（MMP-2 和 MMP-7）、EGFR、收缩蛋白（如肌球蛋白轻链激酶和 MLC II）及其转录激活物的表达和活性，包括核糖体 S6 激酶（P90RSK）和血清反应因子，可能通过细胞外信号调节激酶（ERK1/2）在 VSMCs 中的激活。此外，在胰岛素抵抗的 VSMCs 和 FHRs 的动脉中，通过药理学或小干扰 RNA 方法破坏 MMP-EGFR 信号通路可使收缩蛋白及其转录激活物的表达和活性恢复正常，并防止 FHRs 发生高血压。
我们的数据表明，MMP-EGFR 途径可能是治疗胰岛素抵抗和/或高血糖症（如 2 型糖尿病）相关高血压的潜在靶点。
