體外實驗的數(shù)據(jù)分析證實了一些不同的刺激和分子可以再現(xiàn)心肌重構(gòu)的許多特征，包括心肌細(xì)胞肥大,、胚胎基因的誘導(dǎo),、肌細(xì)胞的凋亡和纖維細(xì)胞的增殖。這些因子中的許多已證實存在于肥大或衰竭的心肌細(xì)胞里,，包括興奮的機(jī)械應(yīng)激,、兒茶酚胺、血管緊張素,、內(nèi)皮素,、肽類生長因子、炎癥細(xì)胞因子,、一氧化氮和氧化應(yīng)激,。
⑴ 機(jī)械應(yīng)激：心肌細(xì)胞肥大和重構(gòu)的最常見刺激是血液動力學(xué)超負(fù)荷。在心肌細(xì)胞水平,，血液動力學(xué)超負(fù)荷可以通過計算周圍室壁壓力表現(xiàn),。收縮期室壁壓力的增加經(jīng)常導(dǎo)致左心室收縮壓的提高，但是如果收縮期室腔容積的增加,，也會出現(xiàn)受收縮壓維持正?；蚪档?。舒張期室壁壓力的提高主要可由室腔擴(kuò)大或是舒張期充盈壓升高引起。
對心肌細(xì)胞而言,，異常的機(jī)械刺激可以直接導(dǎo)致心肌重構(gòu),。在硅膠膜上培養(yǎng)48小時，伸展的心肌細(xì)胞內(nèi)20%的蛋白含量提高到大約30%,，預(yù)示細(xì)胞肥大,。在這種條件下，調(diào)節(jié)細(xì)胞生長的第二信使通路將被激活,，包括鈣內(nèi)流,、磷酸肌醇產(chǎn)生、蛋白激酶C的活化和分裂素激活的蛋白激酶,，也就是早期效應(yīng)基因（如,，c-fos）和胚胎程序（如，prepro-ANF）的誘導(dǎo),。因為在這個實驗中只有肌細(xì)胞出現(xiàn)這個現(xiàn)象,，說明心肌細(xì)胞的機(jī)械變形對生長和基因表達(dá)是一個直接性的刺激。此外,，伸展誘導(dǎo)肽類生長因子的表達(dá)或釋放,，如β-腫瘤生長因子、血管緊張素和內(nèi)皮素,，這些因子通過自分泌或旁分泌的方式作用于肌細(xì)胞和周圍細(xì)胞,。也有證據(jù)表明肌細(xì)胞的伸展可以誘導(dǎo)心肌細(xì)胞的調(diào)亡[12]。
⑵ 交感神經(jīng)系統(tǒng)：交感神經(jīng)活性無疑是涉及心肌重構(gòu)調(diào)節(jié)的主要外源性因素,。體外試驗表明,，去甲腎上腺素—基本的神經(jīng)遞質(zhì)，有刺激心肌細(xì)胞的生長[13-15],，誘導(dǎo)胚胎基因的表達(dá),，下調(diào)鈣相關(guān)基因，β-腫瘤生長因子的表達(dá)的作用,。雖然與去甲腎上腺素相關(guān)的新生的大鼠細(xì)胞肥大主要是由α1-腎上腺素受體途徑介導(dǎo),，但是α1-腎上腺素受體和β-腎上腺素受體途徑與成年大鼠的心肌細(xì)胞肥大有關(guān)。
利用可以過度表達(dá)Gs-蛋白α亞單位的轉(zhuǎn)基因小鼠,，觀察到心肌細(xì)胞凋亡的增長,，表明β-腎上腺素受體途徑在調(diào)節(jié)心力衰竭有作用[16]。同樣,，去甲腎上腺素,，激活β-腎上腺素受體，也被證實引起離體心肌細(xì)胞的死亡[17]。培養(yǎng)的成年大鼠心肌細(xì)胞,，暴露于去甲腎上腺素,，可以產(chǎn)生β-腎上腺素受體途徑介導(dǎo)的凋亡。此外,，去甲腎上腺素能夠通過激活β-腎上腺素受體刺激心肌成纖維細(xì)胞的DNA和蛋白質(zhì)合成[18],。這些結(jié)果表明：去甲腎上腺素有造成病理性的心肌重構(gòu)許多重要特征的作用，包括肥大,、胚胎基因表達(dá)和肌細(xì)胞的凋亡,、纖維細(xì)胞生長和蛋白合成的激活。
⑶ 腎素—血管緊張素系統(tǒng)：與去甲腎上腺素相似,，血管緊張素也可能直接作用心肌細(xì)胞,，獨立于它對血管和代謝的作用，主要影響心肌重構(gòu),。血管緊張素可提高心肌細(xì)胞的蛋白質(zhì)合成和心肌纖維細(xì)胞的DNA合成,。此外，血管緊張素能引起培養(yǎng)的心肌細(xì)胞凋亡[19],。這些作用可以被AT1受體的選擇性抑制劑拮抗,。
完整的腎素—血管緊張素系統(tǒng)(RAS)存在于心肌層，一些環(huán)節(jié)隨著心肌重構(gòu)和衰竭上調(diào),，包括血管緊張素還原酶的活性,、血管緊張素原mRNA的水平和血管緊張素受體的密度[20-22]。存在于心肌細(xì)胞的血管緊張素,，可能是組織血管緊張素的主要來源[23]。有趣的是,，可以證實肌細(xì)胞中的血管緊張素可以通過細(xì)胞的伸展釋放并且介導(dǎo)肌細(xì)胞肥大和基因表達(dá)[23],。這些觀察表明作為與血液動力學(xué)超負(fù)荷相關(guān)的循環(huán)性激素和自分泌/旁分泌介質(zhì)，血管緊張素在病理性的心肌重構(gòu)中扮演重要角色,。
⑷ 內(nèi)皮素：內(nèi)皮素-1是又一個強(qiáng)效的血管收縮肽,，對心肌細(xì)胞的生長和表型有重要影響。培養(yǎng)的大鼠心肌細(xì)胞曝露于內(nèi)皮素24小時,，可出現(xiàn)細(xì)胞肥大和提高和收縮亞單位相關(guān)的肌球蛋白輕鏈-2的表達(dá)[24],。與血管緊張素相似，內(nèi)皮素-1可以由心肌層的許多細(xì)胞產(chǎn)生,，而且內(nèi)皮素-1及其受體在重構(gòu)心肌中表達(dá)上調(diào)[25],。近來，內(nèi)皮素-A亞型受體抑制劑BQ-123被證實可以提高心肌梗死大鼠的存活[26],。綜上所述,，內(nèi)皮素-1通過自分泌或旁分泌介導(dǎo)與血流動力超負(fù)荷引起的心肌重構(gòu)。
原文出處：Am J Cardiol 1997;80(11A):15L–25L
題目：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.
