Fibroblasts and myofibroblasts: what are we talking about?

Cardiac myocytes, although large enough to make up most of the heart volume, are only a minority of cells within the heart with fibroblasts and blood vessel components (endothelial and smooth muscle cells) making up the remainder of the heart. In recent years, there has been increasing interest in the nonmyocyte population within the heart. This is attributable, in part, to our increasing understanding of the biology of the nonmyocyte cell types and additionally it is the result of our awakening realization that these cells are not static but rather that they are dynamic in nature indicating that they play a more active role in cardiac function than previously imagined. Studies now show that fibroblasts are involved in formation of the extracellular matrix and they control the size of the extracellular matrix. Additionally, they participate in the repair process by differentiating into myofibroblasts, which are cells involved in the inflammatory response to injury. Myofibroblasts migrate to the sites of injury where they produce cytokines, thus enhancing the inflammatory response. This review discusses both structural and functional differences between the two cell types and examines the different roles of these two different cell types in the heart.     

Communication signals between cardiac fibroblasts and cardiac myocytes

Interspersed between cardiac myocytes, cardiac fibroblasts serve mainly as a structural support during ventricular wall thickening from embryogenesis until adulthood. Cardiac fibroblasts, however, may also serve as a source of mitogens, extracellular matrix proteins, cytokines, and growth factors that could affect the phenotype of the cardiac myocyte. The crosstalk between cardiac fibroblasts and myocytes is important during cardiac development and remodeling in response to injury. The cell-to-cell communication involves paracrine signals (cytokines and growth factors), direct interactions (connexins and cadherins) as well as indirect interactions (integrin signaling through the extracellular matrix). In this review, known cardiac fibroblast-cardiac myocyte signaling pathways are briefly examined and their effect on the heart during disease progression is discussed. Furthermore, speculations are made regarding the possibility that vascular endothelial growth factor B can serve as an important signaling molecule between cardiac fibroblasts and cardiac myocytes and could promote cardiac function in compromised hearts.     

Verapamil depresses the synthesis of lipoxygenase products by hypoxic cardiac rat fibroblasts in culture

Lipoxygenase metabolites of arachidonic acid are potent chemotactic and vasoconstrictive agents and their local production in the myocardium induces the migration of polymorphonuclear cells into ischemic myocardium. These cells have been shown to play a role in the development of ischemic myocardial lesions. In the present study, the synthesis of arachidonic acid lipoxygenase metabolites by rat cardiac cells in culture and the effect of verapamil were investigated under normal and hypoxic conditions. Myocytes and fibroblasts metabolized exogenous arachidonic acid into 12-HETE and an unidentified metabolite (X). Fibroblasts synthesized significantly greater amounts of 12-HETE than myocytes (P less than 0.01). Hypoxia (glucose-free medium and low PO2) and verapamil (10(-7) M) under normal conditions, did not change metabolite synthesis by either type of cells. Under hypoxia, verapamil decreased significantly 12-HETE and X production by fibroblasts (P less than 0.01 and P less than 0.05), whereas the synthesis in myocytes was not changed. It is concluded that the decrease in lipoxygenase product synthesis under hypoxia by verapamil may contribute to its therapeutic effects on the ischemic heart.     

The cardiac fibroblast: functional and electrophysiological considerations in healthy and diseased hearts

Cardiac fibrosis occurs in a number of cardiovascular diseases associated with a high incidence of arrhythmias. A critical event in the development of fibrosis is the transformation of fibroblasts into an active phenotype or myofibroblast. This transformation results in functional changes including increased proliferation and changes in the release of signaling molecules and extracellular matrix deposition. Traditionally, fibroblasts have been considered to affect cardiac electrophysiology indirectly by physically isolating myocytes and creating conduction barriers. There is now increasing evidence that cardiac fibroblasts may play a direct role in modulating the electrophysiological substrate in diseased hearts. The purpose of this review is to summarize the functional changes associated with fibroblast activation, the membrane currents that have been identified in adult cardiac fibroblasts, and describe recent studies of fibroblast-myocyte electrical interactions with emphasis on the changes that occur with cardiac injury. Further analysis of fibroblast membrane electrophysiology and their interactions with myocytes will lead to a more complete understanding of the arrhythmic substrate. These studies have the potential to generate new therapeutic approaches for the prevention of arrhythmias associated with cardiac fibrosis.     

胰岛素对心脏细胞增殖的影响及其在心肌肥厚中的作用

目的　研究胰岛素对心肌细胞和心肌成纤维细胞增殖的影响 ,探讨其在心肌肥厚中的作用。方法　①乳鼠心肌细胞和心肌成纤维细胞的培养及光镜、电镜和免疫细胞化学染色的鉴定。②两种细胞在不同浓度胰岛素作用下细胞数量、代谢活性与DNA合成 (WST 1、BrdUELISA法 )的测定及细胞周期分析 (流式细胞仪 )。结果　①培养的心脏细胞分别为心肌细胞和成纤维细胞。②胰岛素作用下 ,心肌细胞的数量、WST 1与BrdU的OD值及S +G2 +M期细胞百分比无变化 (P >0 0 5 ) ;而心肌成纤维细胞的数量、WST 1与BrdU的OD值及S +G2 +M期细胞百分比均升高 (P <0 0 1或P <0 0 5 )。结论　胰岛素可促进培养的心肌成纤维细胞增殖 ,可能在心肌肥厚中起重要作用     

Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts

Several clinical trials have shown the beneficial effects of statins in the prevention of coronary heart disease. Additionally, statins promote apoptosis in vascular smooth muscle cells, in renal tubular epithelial cells and also in a variety of cell lines; yet, the effects of statins on cardiac fibroblast and myofibroblast, primarily responsible for cardiac tissue healing are almost unknown. Here, we investigated the effects of simvastatin on cardiac fibroblast and myofibroblast viability and studied the molecular cell death mechanism triggered by simvastatin in both cell types.

Methods

Rat neonatal cardiac fibroblasts and myofibroblasts were treated with simvastatin (0.1-10 μM) up to 72 h. Cell viability and apoptosis were evaluated by trypan blue exclusion method and by flow cytometry, respectively. Caspase-3 activation and Rho protein levels and activity were also determined by Western blot and pull-down assay, respectively.

Results

Simvastatin induces caspase-dependent apoptosis of cardiac fibroblasts and myofibroblasts in a concentration- and time-dependent manner, with greater effects on fibroblasts than myofibroblasts. These effects were prevented by mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate, but not squalene. These last results suggest that apoptosis was dependent on small GTPases of the Rho family rather than Ras.

Conclusion

Simvastatin triggered apoptosis of cardiac fibroblasts and myofibroblasts by a mechanism independent of cholesterol synthesis, but dependent of isoprenilation of Rho protein. Additionally, cardiac fibroblasts were more susceptible to simvastatin-induced apoptosis than cardiac myofibroblasts. Thus simvastatin could avoid adverse cardiac remodeling leading to a less fibrotic repair of the damaged tissues.     

EPAC expression and function in cardiac fibroblasts and myofibroblasts

In the heart, cardiac fibroblasts (CF) and cardiac myofibroblasts (CMF) are the main cells responsible for wound healing after cardiac insult. Exchange protein activated by cAMP (EPAC) is a downstream effector of cAMP, and it has been not completely studied on CF. Moreover, in CMF, which are the main cells responsible for cardiac healing, EPAC expression and function are unknown. We evaluated in both CF and CMF the effect of transforming growth factor β1 (TGF-β1) on EPAC-1 expression. We also studied the EPAC involvement on collagen synthesis, adhesion, migration and collagen gel contraction.     

Effect of age on cardiac excitation–contraction coupling

1. Cardiovascular diseases most commonly occur in the elderly and are a frequent cause of disability or death. However, the effect of age itself on cardiac function is not well understood.
2. Studies in both human and animal hearts indicate that contractile function is unaffected by age while at rest. However, the ability to increase cardiac contractile force during strenuous activities, such as exercise, declines with age.
3. Similar findings have been observed in individual ventricular myocytes isolated from aged hearts. When myocytes are stimulated with β-adrenoceptor agonists or rapid pacing frequencies, aged cells show a much smaller increase in peak contractions and Ca²⁺ transients than young adult cells. In addition, contractions and Ca²⁺ transients are prolonged in aged cells compared with younger cells under these conditions.
4. These observations suggest that the age-related decline in cardiac contractile function originates at the cellular level and may reflect modifications in processes involved in excitation–contraction (EC) coupling.
5. Biochemical studies have shown that there are age-related modifications in the expression, regulation and function of a number of proteins essential to EC coupling in the heart.
6. Functional studies indicate that these changes in EC coupling proteins disrupt Ca²⁺ homeostasis and contribute to decrease in peak contraction and prolongation of contraction duration observed in myocytes from aged hearts.
7. The present review describes modifications in cardiac contractile function that occur in the ageing heart and evaluates underlying alterations in the EC coupling pathway that may be responsible for this decline in contractile function in ageing.     

Cardiac fibroblasts in cell culture systems: myofibroblasts all along?

The cytoarchitecture of the working myocardium is characterized by densely packed cardiomyocytes that are embedded in a three-dimensional network of numerous fibroblasts. Although the importance of cardiac fibroblasts in maintaining an orderly structured extracellular matrix is well recognized, less is known about their potential paracrine and electrotonic interactions with cardiomyocytes. This is partly the result of the complex intermingling of both cell types in vivo that tends to preclude a direct investigation of heterocellular crosstalk. It is for that reason that most of our present knowledge regarding stromal-parenchymal cell interactions is based on culture systems that permit direct access to either cell type. An often disregarded feature of such studies is that cardiac fibroblasts in standard two-dimensional cell culture have a pronounced tendency to undergo a phenotype switch to myofibroblasts. This cell type typically appears in injured hearts where it contributes importantly to fibrotic remodeling. The present review focuses on recent insights into electrical and paracrine crosstalk between myofibroblasts and cardiomyocytes while acknowledging that a comprehensive understanding of stromal-parenchymal cell interactions will depend on future methodological developments that permit retaining the fibroblast phenotype in cell culture systems and that will, most importantly, allow direct investigations of heterocellular crosstalk in intact tissue.     

Cardiomyocytes from human embryonic stem cells

Terminal heart failure is characterized by a significant loss of cardiac myocytes. Stem cells represent a possibility for replacing these lost myocytes but the question of which stem cells are most ideally suited for cell transplantation therapies is still being addressed. Here, we consider human embryonic stem cells (HESC), derived from human embryos in this context. We review the methods used to induce their differentiation to cardiomyocytes in culture, their properties in relation to primary human cardiomyocytes and their ability to integrate into host myocardium. In addition, issues regarding their safety that need addressing before use in cell transplantation therapies, both generally and specifically in relation to the heart, are considered.     

Cardiac hypertrophy: a matter of translation

1. Left ventricular hypertrophy (LVH) of the heart is an adaptive response to sustained increases in blood pressure and hormone imbalances. Left ventricular hypertrophy is associated with programmed responses at the molecular and biochemical level in different subsets of cardiac cells, including the cardiac muscle cells (cardiomyocytes), fibroblasts, conductive tissue and coronary vasculature. 2. Regardless of the initiating cause, the actual increase in chamber enlargement is, in each case, due to an increase in size of a pre-existing cardiomyocyte population, with little or no change in their number; a process referred to as cellular hypertrophy. 3. An accelerated rate of global protein synthesis is the primary mechanism by which protein accumulation increases during cardiomyocyte hypertrophy. In turn, increased rates of synthesis are a result of increased translational rates of existing ribosomes (translational efficiency) and/or synthesis and recruitment of additional ribosomes (translational capacity). 4. The present review examines the relative importance of translational capacity and translational efficiency in the response of myocytes to acute and chronic demands for increased protein synthesis and the role of these mechanisms in the development of LVH.     

Transforming growth factor-beta 1 promotes contraction of collagen gel by cardiac fibroblasts through their differentiation into myofibroblasts

Myofibroblasts and transforming growth factor-beta 1 (TGF-beta 1) are key elements of cardiac tissue fibrosis development. The aim of this study was to determine whether the ability of TGF-beta 1 to affect the contractile activity of cardiac fibroblasts depends on their differentiation into myofibroblasts. Cardiac fibroblasts (from male adult Wistar rats) from passage 2 were therefore cultured to confluency and incubated on a hydrated collagen gel, both with and without TGF-beta 1 (0, 20, 40, 100, 200, 400 or 600 pmol/l), for 1, 2 and 3 days in a Dulbecco's Modified Eagle's Medium (DMEM) without fetal bovine serum (FBS). Growing cultures of cardiac fibroblasts were obtained by incubating second-passage fibroblasts in DMEM with 10% FBS with or without TGF-beta 1 (0 to 600 pmol/l) for 6 days. These fibroblasts were then further incubated on the collagen gel for 1, 2 and 3 days in DMEM without FBS. TGF-beta 1 dose-dependently increased the contraction of collagen gel mediated by cardiac fibroblasts, either added directly to the gel or after growing of the cardiac fibroblasts in the presence of TGF-beta 1 for 6 days, reaching a maximal effect at 100 pmol/l TGF-beta 1. In both culturing conditions, TGF-beta 1 also stimulated the [3H]-thymidine incorporation and the total protein content in the cardiac fibroblasts in the collagen gel lattice. TGF-beta 1 dose-dependently induced an increase in alpha-smooth muscle actin, a marker of myofibroblasts, in both culturing conditions. The TGF-beta 1-induced reduction of area of the collagen gel was negatively correlated to the TGF-beta 1-evoked appearance of alpha-smooth muscle actin in the collagen gel matrix. TGF-beta 1 increased the contractile activity of adult rat cardiac fibroblasts and their ability to differentiate into myofibroblasts. Because contractile activity was correlated with differentiation, the influence of TGF-beta 1 on cardiac fibroblast-induced collagen gel contraction may depend on the promotion of myofibroblast differentiation.     

Functional impairment of cardiac transient outward K+ current as a result of abnormally altered cellular environment

1. Physiological functions of cardiac cells require a normal cellular environment. Under pathological conditions, there is a loss of normal cellular environment due to metabolic perturbations and other abnormalities. To test the hypothesis that cellular environmental stresses can create an electrophysiological substrate for electrical disorders in the heart, we investigated the effects of hypoxia, acidosis and ischaemia on transient outward K+ current (I(to)) in single canine ventricular myocytes. 2. The I(to) was studied because it plays a critical role in initiating cardiac repolarization and, thereby, arrhythmias. It was found that I(to) was significantly depressed by some 30% under hypoxic conditions relative to that in a normal cellular environment with normal Tyrode's solution. 3. Acidosis created by lowering the pH of the external solution from 7.4 to 7.2 produced a substantial (approximately 35%) reduction of the I(to) amplitude. 4. A marked impairment of I(to) function was consistently observed in ischaemic hearts in the canine coronary artery ligation model, with an approximate 30% decrease in the size of I(to). 5. Importantly, the impairment of I(to) under these environmental stresses was largely reversible following restoration to normal conditions. 6. The results of the present study suggest that I(to) is susceptible to changes in the cellular environment and the functional impairment of I(to) under environmental stresses contributes to arrhythmias under relevant pathological conditions of the heart.     

Transforming growth factor-beta 1-induced collagen production in cultures of cardiac fibroblasts is the result of the appearance of myofibroblasts

Transforming growth factor-beta 1 (TGF-beta 1), which appears in high concentrations in fibrotic cardiac tissue, is a potent inductor of tissue collagen deposition and of the differentiation of fibroblasts to myofibroblasts. It is accepted that TGF-beta 1 is a potent stimulator of collagen secretion by fibroblasts. The aim of the present study was to determine which type of cells, fibroblasts and/or myofibroblasts are stimulated, in terms of collagen production, by TGF-beta 1. Therefore, using cultures of second-passage rat cardiac fibroblasts, we investigated the dose- (0.003-15 ng/ml) and time-dependence (2-48 h) of the TGF-beta 1-induced effects on collagen production and on the appearance of myofibroblasts, as estimated by the presence of alpha-smooth muscle actin (alpha-SMA; a marker of myofibroblasts). The reversibility of the TGF-beta 1-stimulated effects was also studied. The dose- and time-dependent stimulation of collagen production was closely associated with the induction of alpha-SMA. TGF-beta 1 did not change the cell phenotype or increase collagen production in rat cardiac fibroblasts cultures after a long incubation (24-28 h) at low concentrations (< 1 ng/ml), or after a short incubation (2-4 h) at high concentrations (1-15 ng/ml). However, after a long incubation at high concentrations, TGF-beta 1 changed the cell phenotype and increased collagen production in these cultures through the differentiation of fibroblasts to myofibroblasts. A maximal increase of collagen production (two-fold, p < 0.001) was observed after incubation of fibroblasts with 15 ng/ml TGF-beta 1 for 48 h. Under these conditions, alpha-SMA was increased by 3.5-fold (p < 0.001) and second-passage cultures of fibroblasts and their offspring in the next passage consisted mainly of myofibroblasts. The stimulation of collagen by 15 ng/ml TGF-beta 1 for 48 h was irreversible. In fact, additional incubation of these second-passage TGF-beta 1-stimulated cultures without TGF-beta 1 for 2 days did not decrease the high activity of collagen production. Moreover, the third-passage offspring of these TGF-beta 1-stimulated fibroblasts cultured without TGF-beta 1 also showed a higher production of collagen compared with control fibroblasts. Furthermore, the increased collagen production in the third-passage fibroblast offspring of the second-passage TGF-beta 1-stimulated fibroblasts could not be further stimulated by TGF-beta 1. Thus, the activity of collagen production in TGF-beta 1-stimulated cultures and in their next passage offspring is not sensitive to TGF-beta 1. Our data suggest that TGF-beta 1-stimulated collagen production in cultures of adult rat cardiac ventricular fibroblasts cannot be explained by a direct stimulation of collagen production, either in fibroblasts or in myofibroblasts. Instead, TGF-beta 1 induces differentiation of fibroblasts to myofibroblasts, the latter having a higher activity for collagen production than the former.     

A current perspective of canstatin,a fragment of type IV collagen alpha 2 chain

Type IV collagen is a main component of basement membrane extracellular matrix. Canstatin, a non-collagenous C-terminal fragment of type IV collagen α2 chain, was firstly identified as an endogenous anti-angiogenic and anti-tumor factor, which also has an anti-lymphangiogenic effect. Then, canstatin has been widely investigated as a novel target molecule for cancer therapy. The anti-angiogenic effect of canstatin may be also useful for the treatment of ocular neovascularization. Recently, we have demonstrated that canstatin, which is abundantly expressed in the heart tissue, exerts various biological activities in cardiac cells. In rat H9c2 cardiomyoblasts, canstatin inhibits isoproterenol- or hypoxia-induced apoptosis. Canstatin plays an important role in modulating voltage-dependent calcium channel activity in rat cardiomyocytes. Canstatin also regulates various biological functions in rat cardiac fibroblasts and myofibroblasts. The expression of canstatin decreases in the infarcted area after myocardial infarction. This review focuses on a current perspective for the roles of canstatin in tumorigenesis, ocular neovascularization and cardiac pathology.     

Adenoviral-mediated expression of dihydropyridine-insensitive L-type calcium channels in cardiac ventricular myocytes and fibroblasts

Cardiac voltage-gated Ca2+ channels regulate the intracellular Ca2+ concentration and are therefore essential for muscle contraction, second messenger activation, gene expression and electrical signaling. As a first step in accessing the structural versus functional properties of the L-type Ca2+ channel in the heart, we have expressed a dihydropyridine (DHP)-insensitive CaV1.2 channel in rat ventricular myocytes and fibroblasts. Following isolation and culture, cells were infected with adenovirus expressing either LacZ or a mutant CaV1.2 channel (CaV1.2DHPi) containing the double mutation (T1039Y & Q1043M). This mutation renders the channel insensitive to neutral DHP compounds such as nisoldipine. The whole-cell, L-type Ca2+ current (ICa) measured in control myocytes was inhibited in a concentration-dependent manner by nisoldipine with an IC50 of 66 nM and complete block at 250 nM. In contrast, ICa in cells infected with AdCaV1.2DHPi was inhibited by only 35% by 500 nM nisoldipine but completely blocked by 50 microM diltiazem. In order to study CaV1.2DHPi in isolation, myocytes infected with AdCaV1.2DHPi were incubated with nisoldipine. Under this condition the cells expressed a large ICa (12 pA/pF) and displayed Ca2+ transients during field stimulation. Furthermore, addition of 2 microM forskolin and 100 microM 3-isobutyl-1-methylxanthine (IBMX), to stimulate protein kinase A, strongly increased IBa in the AdCaV1.2DHPi-infected cells. A Cd2+-sensitive IBa was also recorded in cardiac fibroblasts infected with AdCaV1.2DHPi. Thus, expression of CaV1.2DHPi will provide an important tool in studies of cardiac myocyte and fibroblast function.     

病理状态对心肌细胞及心脏成纤维细胞β3-肾上腺素受体表达的影响

目的 观察与心力衰竭相关的不同病理因素刺激下,Sprague-Dawley（SD）乳鼠心肌细胞和心脏成纤维细胞中 β3-肾上腺素受体（β3-AR）表达变化的差异。方法 分离培养 SD乳鼠心肌细胞和心脏成纤维细胞并行免疫荧光鉴定,分别给予血管紧张素Ⅱ（AngⅡ）及去甲肾上腺素（NE）进行刺激,采用实时荧光定量PCR（qPCR）检测心肌细胞肥大相关基因［心钠肽（ANP）、脑钠肽（BNP）、β-肌球蛋白重链（β-MHC）］、心脏成纤维细胞纤维化相关基因［Ⅰ型胶原蛋白（COL-Ⅰ）、Ⅲ型胶原蛋白（COL-Ⅲ）］及2种细胞中β3-AR的mRNA表达。结果 免疫荧光鉴定显示,分离培养的心肌细胞和心脏成纤维细胞均状态良好。AngⅡ和 NE分别刺激 2种细胞 48 h后,心肌细胞中 ANP、BNP、β-MHC和 β3-AR的表达较对照组明显增加;心脏成纤维细胞中 COL-Ⅰ、COL-Ⅲ表达较对照组明显增加,但 β3-AR的表达没有明显变化。结论 参与心力衰竭发生发展的病理因素 AngⅡ和 NE主要引起心肌细胞的 β3-AR表达增加,而不是心脏成纤维细胞。     

Effects of calcium channel blockers on stress protein synthesis in cardiac myocytes.

The detection of "stress proteins," certain protein groups of 70 or 30 kDa molecular weight synthesized de novo under stress conditions, serves as an assay for monitoring cellular toxicity. Typical toxins inducing stress protein formation in cardiac myocytes are CdCl2 and H2O2. The synthesis of 68, 71, and 30 kDa stress proteins is evoked by CdCl2, and H2O2 stimulates the formation of a 30 kDa protein. When fetal mouse myocardial cells are incubated first with CdCl2 and then with H2O2 or vice versa, an additive effect on stress protein synthesis can be documented. The calcium antagonists diltiazem, verapamil, and nifedipine, at concentrations above 0.05 mg/ml, stimulate the de novo synthesis of a 30 kDa stress protein. After preincubation of the cardiac myocytes with slow calcium channel blockers, the synthesis of the 70 kDa stress protein family evoked by CdCl2 is reduced. In contrast to the increased stress protein synthesis after heart cells are exposed to toxins, preincubation with calcium antagonists reduces the formation of certain stress proteins. These results indicate an interference of calcium channel blocking drugs with stress protein formation in cultured mouse myocardial cells.     

Effects of tanshinone VI on the hypertrophy of cardiac myocytes and fibrosis of cardiac fibroblasts of neonatal rats

The possible effects of tanshinone VI (tsh), a diterpene from the root of Tan-Shen (Salvia miltiorrhiza, Bunge (Labiatae)) on hypertrophy and fibrosis in cultured neonatal rat cardiac myocytes and fibroblasts were examined. Tsh had no significant effect on protein synthesis, which was evaluated by [3H]-leucine incorporation into the acid insoluble fraction in the cells, in the absence of stimulatory factors in cardiac myocytes. The amount of protein produced in cardiac myocytes was increased by 10(-8) M endothelin-1 (ET-1), 10(-6) M phenylephrine (PE), or 10(-8) M insulin-like growth factor-1 (IGF-1), suggesting that hypertrophy of cardiac myocytes in vitro was induced by these factors. The ET-1-, PE-, or IGF-1-induced increase in protein synthesis was attenuated by treatment with 10(-5) M tsh. Treatment with 10(-5) M tsh significantly decreased the synthesis of collagen by cardiac fibroblasts, which was evaluated by [3H]-proline incorpolation into acid-insoluble fraction of the fiblobrasts, in the absence of stimulatory factors for the production. Fetal bovine serum (FBS) or IGF-1 increased collagen synthesis in a concentration-dependent manner. The increase at 5% FBS or 10(-8) M IGF-1 was inhibited by 10(-5) M tsh. Fibroblast-conditioned medium (FB-CM) increased protein synthesis in cardiac myocytes in a concentration-dependent manner (10; - 100 %). Tsh attenuated the FB-CM-induced increase in protein synthesis by cardiac myocytes. These results show that tsh may attenuate the humoral factor-induced hypertrophy of cardiac myocytes and fibrosis of cardiac fibroblasts. The findings suggest that tsh may improve the development of cardiac remodeling under pathophysiological conditions. Abbreviations. ANP:atrial natriuretic peptide DMEM:Dulbecco-modified Eagle's medium ET-1:endothelin-1 FB-CM:fibroblast-conditioned medium FBS:fetal bovine serum IGF-1:insulin-like growth factor-1 PE:phenylephrine tsh:tanshinone VI     

Heart failure and endothelin receptor antagonists.

Cardiac myocytes and vascular endothelial cells produce endothelin-1, which increases the contractility of cardiac muscles and of vascular smooth muscles. Endothelin-1 also exerts long-term effects, such as myocardial hypertrophy, and causes cellular injury in cardiac myocytes. In heart failure, the production of endothelin-1 is markedly increased in the failing heart. Here, evidence that an endothelin receptor antagonist is a useful new drug for the treatment of heart failure is discussed. Long-term treatment with an endothelin receptor antagonist greatly improves the survival rate of animals (rat, hamster, etc.) with chronic heart failure. This beneficial effect is accompanied by amelioration of left ventricular dysfunction. The myocardial endothelin system appears to be a novel and important target for therapeutic intervention in heart failure.