摘要:

The two striated muscle cell types, skeletal and cardiac muscle, express overlapping sets of muscle-specific genes. Activation of muscle-specific transcription in skeletal muscle is controlled by the MyoD family of regulatory factors, which are expressed exclusively in skeletal muscle. Members of the MyoD family share homology within a basic helix-loop-helix (HLH) motif that mediates DNA binding and dimerization and form heterodimers with widely expressed HLH proteins, referred to as E proteins. Although many of the genes that are regulated by members of the MyoD family are also expressed in cardiac muscle, known members of the MyoD family have never been detected in cardiac muscle, suggesting that cardiac myocytes either express unique cell type-specific HLH proteins or rely on a distinct regulatory strategy for activation of cardiac muscle transcription. This review will summarize current knowledge of the mechanisms through which the MyoD family activates skeletal muscle transcription and will consider potential mechanisms that may regulate gene expression in the heart.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Proliferative growth of the ventricular myocyte (cardiomyocyte) is primarily limited to fetal and early neonatal periods of development. In concert with the neonatal “transition” from proliferative to hypertrophic growth, ventricular remodeling of the nonmyocyte compartment is characterized by increased extracellular matrix synthesis/deposition and capillary angiogenesis. A role for locally generated and bioactive ventricular acidic fibroblast growth factor (aFGF) in these processes is proposed and substantiated by the following: 1) colocalization of aFGF peptide and fibroblast growth factor receptor (flg) transcripts to the developing fetal cardiomyocyte by immunohistochemistry, immunoelectron microscopy, and in situ hybridization, 2) continued localization of aFGF peptide and transcripts to the neonatal/mature cardiomyocyte, and 3) localization offlgimmunoreactivity and transcripts to specific neonatal ventricular nonmuscle cell types. Specific ventricular cell types at distinct developmental stages appear to be responsive to ventricular myocyte-derived aFGF (myocytes in the fetal heart and nonmyocytes/endothelial cells in the neonatal heart). These data indicate that expression of aFGF and one of its receptors (flg) are most pronounced in the fetal to early neonatal ventricle, the presence of both suggesting an autocrine/paracrine growth regulatory function. As the animal matures, ventricular capillary angiogenesis may be facilitated by “release” of cardiomyocyte-derived fibroblast growth factors into the surrounding extracellular space/matrix functioning as a “paracrine” angiogenic stimuli. Therefore, the results of our study suggest that myocyte-derived aFGF may function to increase the fetal ventricular cardiomyocyte population in absolute number as well as to facilitate the subsequent increase in capillary angiogenesis that occurs during cardiomyocyte maturation and ventricular remodeling.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The relevance of endothelin in central cardiovascular function was studied in urethane-anesthetized Sprague-Dawley rats. Blood pressure (BP) was monitored intra-arterially, and cerebrospinal fluid (CSF) was collected through an intracisternal catheter for radioimmunoassay of endothelin-1 (ET-1). Endothelin levels in the CSF were significantly higher (39±3 pg/ml) than in plasma (10±3 pg/ml,n=11). ET-1 in CSF or plasma was not affected by systemic infusion of saline, but its levels significantly decreased when a sustained increase in BP was elicited with phenylephrine (14±7 pg/ml in the CSF and 6±4 pg/ml in plasma,n=5). In sinoaortic-denervated animals, phenylephrine failed to reduce CSF endothelin levels. In different experiments, intracisternal administration of ET-1 (10 pmol) evoked an initial decrease in BP and heart rate (HR), followed by pronounced hypertension, bradycardia, and, in 70% of the animals, death from cardiorespiratory failure. Intracisternal administration of endothelin-3 (ET-3, 80 pmol,n=11) evoked only a modest hypotensive and bradycardic response without cardiorespiratory impairment. Microinjection of ET-1 (0.5, 1, 2, 4, and 6 pmol/60 nl) into the nucleus of the solitary tract or area postrema produced a decrease in BP and HR. On the other hand, injection of low concentrations of ET-3 into the nucleus of the solitary tract increased BP and HR (at 2 pmol, 17±3 mm Hg, 14±6 beats per minute,n=7), whereas ET-3 in the area postrema produced a prominent dose-related decrease in BP and HR. In the rostroventrolateral medulla, the lowest doses of ET-1 first modestly increased BP and renal sympathetic nerve activity. These effects were followed by hypotension, bradycardia, increase in respiratory frequency, and further enhancement of sympathetic nerve traffic. In 29% of the animals, these effects were followed by cardiorespiratory arrest. The specificity of the cardiovascular response to endothelin was demonstrated by the inhibitory effects of the receptor antagonist BQ-123. These results demonstrate that endothelin has specific cardiovascular effects in the brainstem of the rat and support a role for endothelin in cardiovascular regulation.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Local accumulation of plasminogen activator inhibitor-1 (PAI-1) in response to thrombosis has been implicated not only in inhibition of fibrinolysis but also in the pathogenesis of vascular disease. To determine whether thrombin, known to be released from thrombi, can induce expression of PAI-1 in vascular smooth muscle, bovine aortic smooth muscle cells were exposed to highly purified bovine thrombin. Thrombin, in the absence of serum, induced production of PAI-1 by bovine aortic smooth muscle cells in a dose-dependent manner. PAI-1 activity in the conditioned media reached a maximum with 12 nM thrombin. Metabolic labeling with [35S]methionine demonstrated that the elaborated PAI-1 was newly synthesized and that it comprised both a cleaved inactive 42-kd form and an uncleaved active 46-kd form. The increase of PAI-1 activity in the media paralleled the thrombin-induced increase in the concentration of the 46-kd form. Preincubation of thrombin with hirudin, a specific inhibitor of thrombin, or with d-phenylalanyl-l-prolyl-l-arginine chloromethyl ketone, an inhibitor of the active site of thrombin, prevented the induction of PAI-1 synthesis. The stimulatory effect of thrombin on PAI-1 synthesis was also evident at the level of expression of mRNA, with steady-state PAI-1 mRNA levels increasing by 100% in 4–8 hours. When the bovine aortic smooth muscle cells were exposed to transforming growth factor-βl, an agonist shown previously to increase PAI-1 synthesis in diverse cell types, synergy with thrombin was evident. Thus, production of PAI-1 by vascular smooth muscle cells is augmented by thrombin, potentially predisposing the cells to persistent thrombi and to vasculopathy at sites of thrombosis and at sites of endothelial injury or denudation.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Ischemic preconditioning renders the heart resistant to infarction by an unknown mechanism. This study tests whether preconditioning may be working through activation of ATP-sensitive potassium channels. If that were the case, then blockade of the channels should eliminate preconditioning's protection, and activation of these channels should mimic it. Thirty minutes of regional coronary ischemia followed by 3 hours of reperfusion caused 38.0±3.7% of the risk zone to become infarcted in control rabbits. Preconditioning with 5-minute ischemia followed by a 10-minute reperfusion before the 30-minute insult caused only 8.8±2.1% infarction, which was a reduction of 29.2% in infarct size by preconditioning (p<0.01 versus control value). Pretreatment with the potassium channel blocker glibenclamide at three different concentrations significantly elevated infarct size in the nonpreconditioned hearts at all doses. Preconditioning, however, continued to limit infarct size by an amount not different from that seen in the control group at all doses of glibenclamide. Pinacidil, a potassium channel agonist, given before a 30-minute ischemic insult resulted in infarct sizes no different from that seen in nonpreconditioned control rabbits. We conclude that ATP-sensitive potassium channels are not involved in preconditioning in the rabbit heart; however, blocking those channels does exacerbate ischemia.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Postischemic ventricular myocardial dysfunction, termed stunning, is characterized by a persistent but ultimately reversible depression of contractile function. The present study was undertaken to investigate the possibilities that reduced contractile force in stunning is due to a decrease in maximal tension-generating capability or to a decrease in the Ca2+sensitivity of the myofilaments. The experiments combine an in vivo open-chest porcine heart model of stunning (n=5) with in vitro measures of myocyte myofilament calcium sensitivity from these same hearts. Regional myocardial function in the left anterior descending coronary artery (LAD) perfusion bed of porcine hearts was measured with transmural ultrasonic crystals. The protocol was 45 minutes of low-flow LAD ischemia at 40% of control flow, followed by 30 minutes of postischemic reperfusion at control aerobic flow. Percent systolic wall thickening decreased to 8±5% of control during ischemia (p<0.05) and returned to 38±8% of control in the postischemic stunned state (p<0.05). Serial endocardial biopsies were obtained from the preischemic and postischemic myocardium in the LAD perfusion bed and from the aerobically perfused myocardium in the circumflex bed. The biopsies were mechanically disrupted, and myocyte-sized preparations of permeabi-lized myocardium were attached to a force transducer and a length-changing device to allow for direct measurement of steady-state tension-pCa (i.e., —log[Ca2+]) relations. The pCa for half-maximal activation of tension, i.e., pCa50, in LAD myocardium decreased from 5.88±0.05 before ischemia to 5.69±0.03 after ischemia (p<0.05); however, maximal Ca2+-activated tension and the slope of the tension-pCa relation were unaffected by the ischemic episode. We conclude that the Ca2+sensitivity of isometric tension is reduced and accounts at least in part for the depressed contractile function of stunned myocardium.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Chronic growth hormone (GH) hypersecretion in rats leads to increased isometric force without affecting the unloaded shortening velocity of isolated cardiac papillary muscles, despite a marked isomyosin shift toward V3. To determine if alterations occurred at the level of the contractile proteins in rats bearing a GH-secreting tumor (GH rats), we examined the mechanical properties of skinned fibers to eliminate the early steps of the excitation-contraction coupling mechanism. We found that maximal active tension and stiffness at saturating calcium concentrations (pCa 4.5) were markedly higher in GH rats than in control rats (tension, 52.9±5.2 versus 38.1±4.6 mN.mm−2,p<0.05; stiffness, 1,105±120 versus 685±88 mN · mm−2· μm−1,p<0.01), whereas values at low calcium concentrations (pCa 9) were unchanged. In addition, the calcium sensitivity of the contractile proteins was slightly but significantly higher in GH rats than in control rats (ΔpCa 0.04,p<0.001). The crossbridge cycling rate, reflected by the response to quick length changes, was lower in GH rats than in control rats (62.0±2.6 versus 77.4±6.6 sec−1,p<0.05), in good agreement with a decrease in the proportion of ce-myosin heavy chains in the corresponding papillary muscles (45.5±2.0% versus 94.6±2.4%,p<0.001). The changes in myosin heavy chain protein phenotype were paralleled by similar changes of the corresponding mRNAs, indicating that the latter occurred mainly at a pretranslational level. These results demonstrate that during chronic GH hypersecretion in rats, alterations at the myofibrillar level contribute to the increase in myocardial contractility observed in intact muscle.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

cAMP content and protein phosphorylation were determined in unlabeled and32P-labeled guinea pig ventricular myocytes. Isoproterenol (10 nM, 37°C, 10 seconds) increased cAMP content (236%) and phospholamban (265%) and troponin I (135%) phosphorylation in ventricular myocytes. When isoproterenol (0–300 nM) and the A,-adenosine receptor agonist (−)-N6-phenylisopropyladenosine (PIA, 1μM) or the A1- and A2-adenosine receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA, 1 μM) were administered simultaneously, both adenosine receptor agonists attenuated phospholamban phosphorylation to approximately the same extent (40%). The EC50value for isoproterenol to phosphorylate phospholamban was 8±1 nM (n=3), which increased to 31±4 nM (n=3) in the presence of PIA or NECA. IC50values for PIA or NECA to decrease the phosphorylation of phospholamban were 30 or 32 nM in 10 nM isoproterenol-stimulated cells and 80 or 85 nM in 30 nM isoproterenol-stimulated cells. Both adenosine receptor agonists failed to inhibit the phosphorylation of troponin I. However, acetylcholine (2 μM) in the presence of 10 nM isoproterenol inhibited phosphorylation of phospholamban as well as troponin I in ventricular cells. These effects were antagonized by 10 μM atropine. The effects of PIA and NECA on phosphorylation were antagonized by the A1-selective adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (1 μM) but not by the A2-selective adenosine receptor antagonist 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4,triazolo(1,5-c)quinazolin-5-imine (1 μM). PIA and NECA did not reduce cAMP levels in isoproterenol-stimulated cells. We conclude that phospholamban phosphorylation was inhibited by A1-adenosine receptor activation and that these effects on phospholamban phosphorylation cannot be explained by a reduction in cAMP levels.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Class III antiarrhythmic agents act by selective prolongation of cardiac action potential duration (APD). Methanesulfonanilide class III agents (e.g., E-4031 and dofetilide) are extremely potent and lengthen action potentials in a “reverse” rate-dependent manner; i.e., effects are greater at low compared with high rates of stimulation. By using the whole-cell current-clamp technique in isolated guinea pig ventricular myocytes, APD was shortened by rapid pacing (244±16 msec at 30 pulses per minute, 166±8 msec at 240 pulses per minute;n=8). Dofetilide (1 μM) prolonged APD more when cells were stimulated at the rate of 30 pulses per minute (44±10-msec increase) than at 240 pulses per minute (21±5-msec increase). We investigated the mechanism of APD prolongation using voltage-clamp techniques. Dofetilide selectively inhibited IKr(IC50, 31.5 nM), defined as the rapidly activating inward rectifying component of net delayed rectifier K+current (IK), without effects on the larger but more slowly activating component of IK(IKs) or on the inward rectifier K+current (IK1). To examine the rate-dependent effects of dofetilide on APD, trains of conditioning pulses to 0 mV (200-msec duration) were applied at either 30 or 240 pulses per minute to mimic the action potential experiments. Test pulses or ramps were given after the conditioning train to quantitate changes in IK1, IKr, or IKs. The magnitude of neither IK1nor IKrwas dependent on the rate of the preceding train of depolarizations. Sensitivity to block of IKrby dofetilide was rate independent. In contrast, the magnitude of IKswas increased by rapid pacing, a result of incomplete deactivation of IKsduring the abbreviated interpulse intervals. It was concluded that APD prolongation by dofetilide is a result of IKrblock; however, incomplete deactivation of IKspartially offsets the rate-independent block of IKrresulting in reverse rate dependence.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Autofluorescence spectroscopy of arterial surfaces provides information about the distribution and composition of atherosclerotic plaques. The aim of the study was to determine whether accumulation of peroxidized lipoproteins in arterial walls, a process postulated to play a role in initiating atherosclerotic changes, can be demonstrated by fluorescence spectroscopy. XeCl excimer laser (308 nm)-induced fluorescence of human aortas containing early lipid-rich noncollagenous lesions exhibited marked red shifts and broadening of the fluorescence spectra compared with spectra from nonatherosclerotic aortas. Similar profiles were observed in spectra obtained from oxidatively modified low density lipoprotein but not native low density lipoprotein. In hypercholesterolemic rabbits with early foam cell lesions, spectral shifts resembled those of oxidized β-very low density lipoprotein, the major lipoprotein accumulating in arteries of rabbits fed cholesterol. XeCl laser-fluorescence spectroscopy of arterial surfaces may be useful for the identification of arteries accumulating modified lipoproteins (oxidized low density lipoprotein), a chemical change indicative of atherosclerosis in its early and probably reversible stages.

ISSN:0009-7330    

出版商:OVID    

年代:1993

数据来源: OVID