Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany.
Cardiovasc Res. 2012 Oct 1;96(1):120-9. doi: 10.1093/cvr/cvs247. Epub 2012 Jul 26.
Hypertension evokes detrimental changes in the arterial vessel wall that facilitate stiffening and thus lead to a further rise in mean blood pressure, eventually causing heart failure. The underlying pathophysiological remodelling process is elicited by an increase in wall stress (WS) and is strictly dependent on the activation of vascular smooth muscle cells (SMC). However, it remains unclear as to why these cells fail to maintain their contractile and quiescent phenotype in a hypertensive environment.
In this context, we reveal that the knockdown of myocardin--a pivotal transcriptional determinant of the contractile SMC phenotype--is sufficient to induce SMC proliferation. In line with this observation, immunofluorescence analysis of the media of remodelling arteries from hypertensive mice demonstrated a significant decrease in the abundance of myocardin and an increase in SMC proliferation. Subsequent analyses of isolated perfused mouse arteries and human cultured SMCs exposed to cyclic stretch (i.e. mimicking one component of WS) suggested that this biomechanical force facilitates serine phosphorylation of myocardin. Furthermore, this biomechanical stimulus promotes rapid translocation of myocardin from the nucleus to the cytoplasm, inhibits its mRNA expression, and causes proteasomal degradation of the cytoplasmic protein.
Collectively, these findings suggest that hypertension negates the activity of myocardin in SMCs on multiple levels, hence eliminating a crucial determinant of SMC quiescence. This mechanism may control the initial switch from the contractile towards the synthetic SMC phenotype during hypertension and may offer an interesting novel approach to prevent cardiovascular disease.
高血压会引起动脉血管壁的有害变化，使血管壁变硬，从而导致平均血压进一步升高，最终导致心力衰竭。这种潜在的病理重塑过程是由壁面应力（WS）的增加引起的，并且严格依赖于血管平滑肌细胞（SMC）的激活。然而，目前尚不清楚为什么这些细胞在高血压环境中无法维持其收缩和静止表型。
在这方面，我们揭示了肌球蛋白结合蛋白 C（myocardin）的敲低足以诱导 SMC 增殖，而 myocardin 是收缩型 SMC 表型的关键转录决定因素。与这一观察结果一致，对高血压小鼠重塑动脉中层的免疫荧光分析表明，myocardin 的丰度显著降低，SMC 增殖增加。随后对分离的灌注小鼠动脉和暴露于循环拉伸（即模拟 WS 的一个组成部分）的人培养 SMC 的分析表明，这种生物力学力促进了 myocardin 的丝氨酸磷酸化。此外，这种生物力学刺激促使 myocardin 从核快速易位到细胞质，抑制其 mRNA 表达，并导致细胞质蛋白的蛋白酶体降解。
总的来说，这些发现表明，高血压在多个层面上否定了 SMC 中 myocardin 的活性，从而消除了 SMC 静止的一个关键决定因素。该机制可能控制了高血压期间从收缩型向合成型 SMC 表型的初始转变，并可能为预防心血管疾病提供一种有趣的新方法。
