$beta;-Adrenergic stimulation of cardiac non-myocytes increases non-myocyte growth factor production (original) (raw)
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α1-Adrenergic stimulation of FGF-2 promoter in cardiac myocytes and in adult transgenic mouse hearts
American Journal of Physiology Heart and Circulatory Physiology, 1999
stimulation of FGF-2 promoter in cardiac myocytes and in adult transgenic mouse hearts. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H826-H833, 1999.-Fibroblast growth factor (FGF-2), a mitogenic, angiogenic, and cardioprotective agent, is reported to be released from the postnatal heart by a mechanism of transient remodeling of the sarcolemma during contraction. This release can be increased with adrenergic stimulation. RNA blotting was used to assess whether FGF-2 synthesis in neonatal rat cardiomyocytes might also be regulated by adrenergic stimulation. FGF-2 RNA levels were increased after treatment with norepinephrine for 6 h or with the ␣-adrenergic agonist phenylephrine for 48 h. To assess an effect on transcription, neonatal rat cardiomyocytes were transfected with a hybrid rat FGF-2 promoter/luciferase gene (Ϫ1058FGFp.luc) and treated with norepinephrine or phenylephrine for 6 or 48 h, respectively. FGF-2 promoter activity was increased two-to sevenfold in an ␣ 1-specific manner. Putative phenylephrine-responsive elements (PEREs) were identified at positions Ϫ780 and Ϫ761 relative to a major transcription initiation site. However, deletion analysis of Ϫ1058FGFp.luc showed that the phenylephrine response was independent of the putative PEREs, cell contraction, and Ca 2ϩ influx. In transgenic mice expressing Ϫ1058FGFp.luc, a significant three-to sevenfold stimulation of FGF-2 promoter activity was detected in the hearts of two independent lines 6 h after intraperitoneal administration of phenylephrine (50 mg/kg). This increase was still apparent at 24 h but was not detected at 48 h posttreatment. Analysis of FGF-2 mRNA in normal mouse hearts revealed accumulation of the 6.1-kb transcript at 24 h. Control of local FGF-2 synthesis at the transcriptional level through adrenergic stimulation may be important in the response to injury as well as in the maintenance of a healthy myocardium. basic fibroblast growth factor; rat fibroblast growth factor-2 gene; phenylephrine; gene transfer FIBROBLAST GROWTH FACTOR (FGF)-2, also known as basic FGF, is a mitogenic and angiogenic protein that has been found in all tissues examined thus far (3, 16). The effects of FGF-2 are exerted through cell-surface, high-affinity tyrosine kinase receptors (FGFR) and low-affinity sites consisting of heparan sulfate proteoglycans (13, 20). Receptors for FGF-2 (FGFR-1) are present in the embryonic and adult heart (15, 17, 22, 23) and were shown to be essential for normal heart development (26). Although FGF-2 is present in the heart into adulthood (15, 23), its role in the postnatal heart is less clear. FGF-2 is found intracellularly as well as outside the cell, where it is able to exert its effect on cell-surface receptors. However, the mechanism for
American Journal of Physiology-Heart and Circulatory Physiology, 2002
Transforming growth factor-β1(TGF-β1) promotes or inhibits cell proliferation and induces fibrotic processes and extracellular matrix production in numerous cell types. Several cardiac diseases are associated with an increased expression of TGF-β1mRNA, particularly during the transition from stable cardiac hypertrophy to heart failure. In vitro studies suggest a link between TGF-β1signaling and the β-adrenergic system. However, the in vivo effects of this growth factor on myocardial tissue have been poorly identified. In transgenic mice overexpressing TGF-β1(TGF-β), we investigated the in vivo effects on cardiac morphology, β-adrenergic signaling, and contractile function. When compared with nontransgenic controls (NTG), TGF-β mice revealed significant cardiac hypertrophy (heart weight, 164 ± 7 vs. 130 ± 3 mg, P < 0.01; heart weight-to-body weight ratio, 6.8 ± 0.3 vs. 5.1 ± 0.1 mg/g, P < 0.01), accompanied by interstitial fibrosis. These morphological changes correlated with a...
Angiogenesis, 2000
Norepinephrine has growth-promoting effects in cardiac myocytes. The present study in cultured neonatal rat cardiac myocytes tested the hypothesis that norepinephrine also stimulates expression of vascular endothelial growth factor (VEGF), an important angiogenic factor. As assessed by polymerase chain reaction cardiac myocytes and nonmyocytes expressed all three isoforms of rat VEGF, with the short isoform (VEGF121) preferentially expressed in non-myocytes. When cardiac myocytes were stimulated with 1 lM norepinephrine for 24 h in the presence or absence of the specific a-and b-adrenoceptor antagonists prazosin and propranolol, respectively, VEGF mRNA levels and splice variant pattern did not change, whereas atrial natriuretic peptide mRNA levels increased 3 to 4-fold. CoCl 2 increased VEGF mRNA levels in cardiac myocytes five-fold. When cardiac myocytes were cultured with conditioned medium from non-myocytes that had been stimulated with norepinephrine for 24 h VEGF mRNA increased 2-fold. The increase was blocked by antibodies neutralizing TGFb. These data suggest that norepinephrine stimulates myocardial angiogenesis by a paracrine mechanism that involves cardiac non-myocytes and TGFb.
Epidermal growth factor stimulates cAMP accumulation in cultured rat cardiac myocytes
Journal of Cellular Physiology, 1992
We have previously shown that epidermal growth factor (EGF) augments cAMP accumulation in the heart and stimulates cardiac adenylyl cyclase via a G protein mediated mechanism (Nair et al., 1989). More recently, employing an antibody against the carboxy-terminus decapeptide of Gsα, we have demonstrated that Gsα mediates the effects of EGF on cardiac adenylyl cyclase (Nair et al., 1990). Since the heart comprises of a variety of cell types, the purpose of the studies presented here was to determine whether or not the effects of EGF on adenylyl cyclase were mediated in cardiac myocytes or noncardiomyocytes. Therefore, cultures of ventricular cardiomyocytes and noncardiomyocytes from neonatal rat hearts were established and characterized. Apart from the differences in cellular morphology, cardiomyocytes but not the noncardiomyocytes employed in our studies expressed the α- and β-myosin heavy chain (MHC) mRNA and the β-MHC protein. Additionally, as described previously, treatment of cardiomyocytes with thyroid hormone increased α-MHC mRNA and decreased the expression of β-MHC mRNA, indicating that the cardiomyocytes employed in our studies were responding in a physiologically relevant manner. EGF in a time-dependent manner increased cAMP accumulation in the cardiomyocytes but not in noncardiomyocytes. Maximum and half-maximum effects were observed at 100 nM and 2 nM concentrations of EGF, respectively. As determined by the presence of immuno-reactive EGF receptors and tyrosine phosphorylation of the 170 kDa protein in membranes of cardiomyocytes and noncardiomyocytes, both the cell populations contained functional EGF receptors. Therefore, the differential effects of EGF on cAMP accumulation in the two cell populations appear to be due to differential coupling of the EGF receptors to the adenylyl cyclase system rather than the absence of EGF receptors in noncardiomyocytes. Consistent with our previous findings in isolated membranes and perfused rat hearts, EGF-elicited increase in cAMP accumulation in cardiomyocytes did not involve activation of β-adrenoreceptors and was abolished by prior treatment of cells with cholera toxin. Overall, our findings demonstrate that EGF-elicited increase in cAMP accumulation in the heart is the reflection of changes in cAMP content of cardiomyocytes and not noncardiomyocytes.
Hypertension, 2004
Transforming growth factor-β (TGF-β) is a ubiquitous growth-regulating protein with an essential role in tissue repair and formation of extracellular matrix (ECM). To better understand the role of different isoforms of TGF-β in the cardiac remodeling process induced by norepinephrine (NE), the expression of TGF-β1, TGF-β2, and TGF-β3 was studied and compared with the expression of collagen. NE (0.1 mg/kg · h) was intravenously infused in female and male Sprague-Dawley rats for several time periods, and freshly obtained ventricular myocardium after 1 day was dissociated into myocyte and nonmyocyte fractions. Prazosin (0.1 mg/kg · h) and metoprolol (1 mg/kg · h) were used to block α- and β-adrenoceptors, respectively. After NE infusion, the three isoforms of TGF-β were differentially induced as far as the magnitude and the time course is concerned. The increased expression of TGF-β2 started earlier with a maximum after 12 hours and was more pronounced (10-fold elevation) than that of ...
Life Sciences, 2018
Paracrine factors, including growth factors and cytokines, released from cardiac myocytes following β-adrenergic receptor (β-AR) stimulation regulate cardiac fibroblasts. Activated cardiac fibroblasts have the ability to increase collagen synthesis, cell proliferation and myofibroblast differentiation, leading to cardiac fibrosis. However, it is unknown which β-AR subtypes and signaling pathways mediate the upregulation of paracrine factors in cardiac myocytes. In this study, we demonstrated that sustained stimulation of β-ARs significantly induced synthesis and secretion of growth factors, including connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF), via the cAMP-dependent and protein kinase A (PKA)-dependent pathways. In addition, isoproterenol (ISO)-mediated synthesis and secretion of CTGF and VEGF through the β 1-AR and β 2-AR subtypes. Paracrine factors released by cardiac myocytes following sustained β-AR stimulation are necessary for the induction of cell proliferation and synthesis of collagen I, collagen III and α-smooth muscle actin (α-SMA) in cardiac fibroblasts, confirming that β-AR overstimulation of cardiac myocytes induces cardiac fibrosis by releasing several paracrine factors. These effects can be antagonized by β-blockers, including atenolol, metoprolol, and propranolol. Thus, the use of β-blockers may have beneficial effects on the treatment of myocardial fibrosis in patients with heart failure.
Hypertension, 2004
Transforming growth factor- (TGF-) is a ubiquitous growth-regulating protein with an essential role in tissue repair and formation of extracellular matrix (ECM). To better understand the role of different isoforms of TGF- in the cardiac remodeling process induced by norepinephrine (NE), the expression of TGF-1, TGF-2, and TGF-3 was studied and compared with the expression of collagen. NE (0.1 mg/kg ⅐ h) was intravenously infused in female and male Sprague-Dawley rats for several time periods, and freshly obtained ventricular myocardium after 1 day was dissociated into myocyte and nonmyocyte fractions. Prazosin (0.1 mg/kg ⅐ h) and metoprolol (1 mg/kg ⅐ h) were used to block ␣and -adrenoceptors, respectively. After NE infusion, the three isoforms of TGF- were differentially induced as far as the magnitude and the time course is concerned. The increased expression of TGF-2 started earlier with a maximum after 12 hours and was more pronounced (10-fold elevation) than that of the other two isoforms, with a clear specificity for the left ventricle in female hearts. This specificity was also seen in male rats with 16-fold elevation of TGF-2 after 1 day of NE-stimulation. The increase of TGF-2 was significant only in the myocyte fraction obtained from female as well as from male hearts. The expression of the mRNA of all TGF- isoforms of collagen type I and type III, and of the matrix metalloproteinase (MMP)-2 and its inhibitor TIMP-2 was reduced predominantly by ␣-adrenoceptor blockade with prazosin. The increase in TGF- isoforms correlated with that of the mRNA expression of collagens, MMP-2 and TIMP-2. (Hypertension. 2004;44:410-418.