体外实验的数据分析证实了一些不同的刺激和分子可以再现心肌重构的许多特征，包括心肌细胞肥大、胚胎基因的诱导、肌细胞的凋亡和纤维细胞的增殖。这些因子中的许多已证实存在于肥大或衰竭的心肌细胞里，包括兴奋的机械应激、儿茶酚胺、血管紧张素、内皮素、肽类生长因子、炎症细胞因子、一氧化氮和氧化应激。
⑴ 机械应激：心肌细胞肥大和重构的最常见刺激是血液动力学超负荷。在心肌细胞水平，血液动力学超负荷可以通过计算周围室壁压力表现。收缩期室壁压力的增加经常导致左心室收缩压的提高，但是如果收缩期室腔容积的增加，也会出现受收缩压维持正常或降低。舒张期室壁压力的提高主要可由室腔扩大或是舒张期充盈压升高引起。
对心肌细胞而言，异常的机械刺激可以直接导致心肌重构。在硅胶膜上培养48小时，伸展的心肌细胞内20%的蛋白含量提高到大约30%，预示细胞肥大。在这种条件下，调节细胞生长的第二信使通路将被激活，包括钙内流、磷酸肌醇产生、蛋白激酶C的活化和分裂素激活的蛋白激酶，也就是早期效应基因（如，c-fos）和胚胎程序（如，prepro-ANF）的诱导。因为在这个实验中只有肌细胞出现这个现象，说明心肌细胞的机械变形对生长和基因表达是一个直接性的刺激。此外，伸展诱导肽类生长因子的表达或释放，如β-肿瘤生长因子、血管紧张素和内皮素，这些因子通过自分泌或旁分泌的方式作用于肌细胞和周围细胞。也有证据表明肌细胞的伸展可以诱导心肌细胞的调亡[12]。
⑵ 交感神经系统：交感神经活性无疑是涉及心肌重构调节的主要外源性因素。体外试验表明，去甲肾上腺素—基本的神经递质，有刺激心肌细胞的生长[13-15]，诱导胚胎基因的表达，下调钙相关基因，β-肿瘤生长因子的表达的作用。虽然与去甲肾上腺素相关的新生的大鼠细胞肥大主要是由α1-肾上腺素受体途径介导，但是α1-肾上腺素受体和β-肾上腺素受体途径与成年大鼠的心肌细胞肥大有关。
利用可以过度表达Gs-蛋白α亚单位的转基因小鼠，观察到心肌细胞凋亡的增长，表明β-肾上腺素受体途径在调节心力衰竭有作用[16]。同样，去甲肾上腺素，激活β-肾上腺素受体，也被证实引起离体心肌细胞的死亡[17]。培养的成年大鼠心肌细胞，暴露于去甲肾上腺素，可以产生β-肾上腺素受体途径介导的凋亡。此外，去甲肾上腺素能够通过激活β-肾上腺素受体刺激心肌成纤维细胞的DNA和蛋白质合成[18]。这些结果表明：去甲肾上腺素有造成病理性的心肌重构许多重要特征的作用，包括肥大、胚胎基因表达和肌细胞的凋亡、纤维细胞生长和蛋白合成的激活。
⑶ 肾素—血管紧张素系统：与去甲肾上腺素相似，血管紧张素也可能直接作用心肌细胞，独立于它对血管和代谢的作用，主要影响心肌重构。血管紧张素可提高心肌细胞的蛋白质合成和心肌纤维细胞的DNA合成。此外，血管紧张素能引起培养的心肌细胞凋亡[19]。这些作用可以被AT1受体的选择性抑制剂拮抗。
完整的肾素—血管紧张素系统(RAS)存在于心肌层，一些环节随着心肌重构和衰竭上调，包括血管紧张素还原酶的活性、血管紧张素原mRNA的水平和血管紧张素受体的密度[20-22]。存在于心肌细胞的血管紧张素，可能是组织血管紧张素的主要来源[23]。有趣的是，可以证实肌细胞中的血管紧张素可以通过细胞的伸展释放并且介导肌细胞肥大和基因表达[23]。这些观察表明作为与血液动力学超负荷相关的循环性激素和自分泌/旁分泌介质，血管紧张素在病理性的心肌重构中扮演重要角色。
⑷ 内皮素：内皮素-1是又一个强效的血管收缩肽，对心肌细胞的生长和表型有重要影响。培养的大鼠心肌细胞曝露于内皮素24小时，可出现细胞肥大和提高和收缩亚单位相关的肌球蛋白轻链-2的表达[24]。与血管紧张素相似，内皮素-1可以由心肌层的许多细胞产生，而且内皮素-1及其受体在重构心肌中表达上调[25]。近来，内皮素-A亚型受体抑制剂BQ-123被证实可以提高心肌梗死大鼠的存活[26]。综上所述，内皮素-1通过自分泌或旁分泌介导与血流动力超负荷引起的心肌重构。
原文出处：Am J Cardiol 1997;80(11A):15L–25L
题目：Molecular and Cellular Mechanisms ofMyocardial Failure
原文：STIMULI AND MEDIATORS FOR MYOCARDIAL REMODELING
Interpretation of in vitro data demonstrates that several different stimuli and molecules can reproduce various features of myocardial remodeling, including myocyte hypertrophy, the induction of fetal genes, apoptosis of myocytes, and proliferation of fibroblasts (Figure 1). Many of these factors may already be present in hypertrophied or failing myocardium, including increased mechanical stress, catecholamines, angiotensin, endothelin, peptide growth factors, inflammatory cytokines, nitric oxide, and oxidative stress.
Mechanical stress: The most common stimulus for myocardial hypertrophy and remodeling is hemodynamic overload. At the level of the cardiac myocyte, hemodynamic overload can be approximated by calculating circumferential wall stress. An increase in systolic wall stress most often results from an increase in left ventricular systolic pressure, but it may also occur with a normal or decreased systolic pressure if systolic chamber volume is increased. Diastolic wall stress is generally increased as the result of chamber dilation and/or an increase in diastolic filling pressure. Abnormal mechanical stresses on cardiac myocytes may be a direct stimulus for myocardial remodeling. Stretching cardiac myocytes by 20% on a silastic membrane for 48 hours increases protein content by approximately 30%, indicative of hypertrophy.41 Under these conditions, there is activation of second messenger pathways that may regulate cell growth, including calcium influx, inositol phosphate generation, activation of protein kinase-C and mitogen activated protein kinase, as well as the induction of early response genes (e.g., c-fos) and fetal genes (e.g., prepro-ANF). Because only myocytes were present in this experiment, these findings suggest that mechanicaldeformation of the myocyte can be a direct stimulus for growth and gene expression. In addition,stretching induces the expression or release of peptide growth factors such as tumor growth factor-b, angiotensin,and endothelin, which could act in an autocrine or paracrine manner on myocytes and surrounding cells. There is also evidence that mechanical stretch of myocardium can result in apoptosis of cardiacmyocytes.
Sympathetic nervous system: Sympathetic nerve activity is the most clearly identifiable extrinsic factor implicated in the regulation of myocardial remodeling. In vitro, the primary sympathetic neurotransmitter, norepinephrine, stimulates growth of cardiac myocytes, reinduction of fetal genes, downregulation of calcium-regulating genes (Satoh and Colucci, unpublished
data), and the expression of tumor growth factor-b.Although the hypertrophic response to norepinephrine is primarily mediated by the a1-adrenergic pathway in neonatal rat myocytes, both the a1- and b-adrenergic receptor pathways are linked to hypertrophy in adult myocytes.In transgenic mice overexpressing the GS-protein a subunit, there is an increased rate of myocyte apoptosis, suggesting that the b-adrenergic pathway could play a role in mediating myocardial failure.45 Likewise,
norepinephrine, acting via b-adrenergic receptors, has been proved to cause the death of cardiac myocytes in vitro.46 Recently, we found that exposing myocytes cultured from the adult rat heart to norepinephrine produces apoptosis via a b-adrenergic receptor-mediated pathway。In addition to an effect on myocytes, norepinephrine can stimulate DNA and protein synthesis in cardiac fibroblasts in vitro via activation of b-adrenergic receptors (Figure 4). These observations suggest that norepinephrine has the ability to cause many of the central features of pathologic myocardial remodeling, including hypertrophy, fetal gene expression and apoptosis of myocytes, and activation of fibroblast growth and protein synthesis.
Renin–angiotensin–system: Similarly to norepinephrine, angiotensin has the potential to act directly on cardiac cells, independently of its vascular and metabolic actions, thereby affecting myocardial remodeling. Angiotensin increases protein synthesis in cardiac myocytes and DNA synthesis in cardiac fibroblasts. In addition, angiotensin can cause apoptosis in cardiac myocytes in culture. Both effects can be blocked by an antagonist selective for the AT1 receptor.
The complete renin–angiotensin system (RAS) is represented in the myocardium, and several components are upregulated with myocardial remodeling or failure, including angiotensin-converting enzyme activity, the level of angiotensinogen mRNA, and the density of angiotensin receptors.Angiotensin can be found in cardiac myocytes, which thus may be a source of tissue angiotensin.Interestingly, there is evidence that myocyte angiotensin is released by stretch of the cell and can mediate the effects of stretching on myocyte hypertrophy and gene expression. These observations suggest that angiotensin could play an important role in pathologic myocardial remodeling, both as a circulating hormone and as an autocrine/paracrine mediator produced in response to hemodynamic overload.
Endothelin: Endothelin-1 is another potent vasoconstrictor peptide that can exert important effects on cardiac myocyte growth and phenotype. In rat cardiac myocytes in culture, exposure to endothelin-1 for 24 hours causes cellular hypertrophy and increases the expression of myosin light chain-2 organized into contractile units.7 Similar to angiotensin, endothelin-1 can be produced by a variety of cells in the myocardium, and both endothelin-1 and its receptors are upregulated in remodeled myocardium. Recently, inhibition of the endothelium-A receptor subtype with BQ-123 has been demonstrated to increase survival in rats after myocardial infarction. Taken together, these findings suggest that endothelin-1 could act as an autocrine/paracrine mediator of myocardial remodeling in response to hemodynamic overload.
