|
1. |
Molecular Characterization of Angiotensin II‐Induced Hypertrophy of Cardiac Myocytes and Hyperplasia of Cardiac Fibroblasts Critical Role of the AT1Receptor Subtype |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 413-423
Jun-ichi Sadoshima,
Seigo Izumo,
Preview
|
PDF (13395KB)
|
|
摘要:
Increasing evidence suggests that angiotensin II (Ang II) may act as a growth factor for the heart. However, direct effects of Ang II on mammalian cardiac cells (myocytes and nonmyocytes), independent of secondary hemodynamic and neurohumoral effects, have not been well characterized. Therefore, we analyzed the molecular phenotype of cultured cardiac cells from neonatal rats in response to Ang II. In addition, we examined the effects of selective Ang II receptor subtype antagonists in mediating the biological effects of Ang II. In myocyte culture, Ang II caused an increase in protein synthesis without changing the rate of DNA synthesis. In contrast, Ang II induced increases in protein synthesis, DNA synthesis, and cell number in nonmyocyte cultures (mostly cardiac fibroblasts). The Ang II-induced hypertrophic response of myocytes and mitogenic response of fibroblasts were mediated primarily by the AT1receptor. Ang II caused a rapid induction of many immediate-early genes (c-fos, c-jun, jun B, Egr-l, and c-myc) in myocyte and nonmyocyte cultures. Ang II induced “late” markers for cardiac hypertrophy, skeletal α-actin and atrial natriuretic factor expression, within 6 hours in myocytes. Ang II also caused upregulation of the angiotensinogen gene and transforming growth factor-β1gene within 6 hours. Induction of immediate-early genes, late genes, and growth factor genes by Ang II was fully blocked by an AT1receptor antagonist but not by an AT2receptor antagonist. These results indicate that (1) Ang II causes hypertrophy of cardiac myocytes and mitogenesis of cardiac fibroblasts, (2) the phenotypic changes of cardiac cells in response to Ang II in vitro closely mimic those of growth factor response in vitro and of load-induced hypertrophy in vivo, (3) all biological effects of Ang II examined here are mediated primarily by the AT1receptor subtype, and (4) Ang II may initiate a positive-feedback regulation of cardiac hypertrophic response by inducing the angiotensinogen gene and transforming growth factor-β1gene.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
2. |
Signal Transduction Pathways of Angiotensin II‐Inducedc‐fosGene Expression in Cardiac Myocytes In Vitro Roles of Phospholipid‐Derived Second Messengers |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 424-438
Jun-ichi Sadoshima,
Seigo Izumo,
Preview
|
PDF (3137KB)
|
|
摘要:
Angiotensin II (Ang II) causes a rapid induction of immediate-early genes and hypertrophy in the cardiac myocyte. However, the signaling mechanism of Ang II-induced immediate-early gene expression in cardiac myocytes has not been characterized. Therefore, we examined signal transduction of Ang II in neonatal rat cardiac myocytes, usingc-fosgene expression as a model system. Transient transfection ofc-fosreporter gene constructs indicated that the serum response element is not only required but also sufficient for Ang II-induced activation of thec-fospromoter. Ang II is known to cause an increase in [Ca2+]i. We found that Ang II also causes a small increase in cAMP in cardiac myocytes. However, the Ca2+/cAMP response element of thec-fosgene was not sufficient to confer Ang II responsiveness to thec-fospromoter, and inhibitors of protein kinase A had no effects on Ang II-inducedc-fosexpression. On the other hand, chelating intracellular Ca2+with BAPTA-AM inhibited Ang II-inducedc-fosexpression in a dose-dependent manner, suggesting that Ca2+is required for Ang II-induced signaling. Measurements of phospholipid-derived second messengers revealed that Ang II increased production of inositol trisphosphate, diacylglycerol, phosphatidic acid, and arachidonic acids, resulting in a sustained increase in protein kinase C activity. This and other evidence suggest that Ang II activates phospholipase C, phospholipase D, and possibly phospholipase A2. All of these second-messenger systems are activated through the AT1receptor. Pharmacological inhibition of phospholipase C or downregulation of protein kinase C significantly suppressed Ang II-inducedc-fosexpression. In conclusion, Ang II activates multiple phospholipid-derived second-messenger systems via the AT1receptor in cardiac myocytes. Among these second-messenger systems, phospholipase C and protein kinase C seem essential for Ang II-inducedc-fosgene expression, whereas Ca2+may play a permissive role. Finally, the “Ang II response element” of thec-fosgene maps to the protein kinase C-dependent portion of the serum response element.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
3. |
Rat Angiotensin II (Type 1A) Receptor mRNA Regulation and Subtype Expression in Myocardial Growth and Hypertrophy |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 439-447
Junichi Suzuki,
Hiroaki Matsubara,
Masaya Urakami,
Mitsuo Inada,
Preview
|
PDF (5282KB)
|
|
摘要:
Two subtypes of angiotensin II (Ang II) receptors (AT1and AT2) are distinguished by using the respective specific antagonists. In the present study, we report the regulation of cardiac AT1type A (AT1A) receptor mRNA levels and the expression pattern of AT1and AT2receptors in the growth of the heart and the development and regression of cardiac hypertrophy. The ventricular AT1AmRNA level and the density of Ang II receptors at the neonatal period were significantly increased (3.5-fold and 2.5-fold, respectively) and then downregulated with maturation. The cardiac hypertrophy established in spontaneously hypertensive rats or two-kidney one-clip renovascular hypertensive rats resulted in substantial increases in ventricular ATMAmRNA levels (threefold) and Ang II receptor densities (twofold) as compared with those in respective control rats, whereas the receptor affinity was similar. The proportion of AT1and AT2subtypes in the specific Ang II binding in ventricular membranes prepared from normal adult rats was nearly equal. This proportion did not change significantly in the development of myocardial hypertrophy. The regression of cardiac hypertrophy by the normalization of elevated blood pressure completely reversed the increased levels of AT1AmRNA and the receptor density to the control level. Thus, AT1and AT2receptors are present in rat ventricular myocardium, and their expression is developmentally regulated and upregulated in response to hypertrophic change. Ang II action exerted through the increased number of Ang II receptors may contribute to the growth of the heart and thus to the maintenance of established hypertrophy as one of the hormones involved in hypertrophy development.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
4. |
Effects of Adenosine and Its Analogues on Isolated Intracerebral Arterioles Extraluminal and Intraluminal Application |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 448-457
Al Ngai,
H. Winn,
Preview
|
PDF (1910KB)
|
|
摘要:
We evaluated the responses of brain parenchymal arterioles to intraluminal and extraluminal application of adenosine and its analogues. Intracerebral arterioles (28.4- to 60.3 -μm diameter) were isolated from Sprague-Dawley rats, cannulated with micropipettes, and perfused in vitro. Both extraluminal and intraluminal adenosine, 5′-(N-ethylcarboxamido)adenosine (NECA),R-N6-(phenylisopropyl)adenosine (R-PIA), and S-N6-(phenylisopropyl)adenosine (S-PIA) elicited concentration-dependent dilation of these arterioles, but intraluminal application was less potent and efficacious than extraluminal application. Inosine was not vasoactive. A common order of agonist potency (NECA >adenosine >R-PIA ≥ S-PIA) was determined for both extraluminal and intraluminal application. Theophylline (10,μM) caused a right ward shift of the adenosine concentration-response curve and a 50-fold reduction in potency. Intraluminal theophylline was one sixth as effective as extraluminal theophylline in antagonizing the extraluminal adenosine response, whereas intraluminal 8-sulfophenyltheophylline, a polar theophylline derivative, was ineffective. Polyadenylic acid (PolyA, 1 μM), an adenosine polymer that does not penetrate the endothelium, induced a dilation of 44.2 ± 5.3% when applied extraluminally but had no effect when infused intraluminally. The dilator effect of PolyA was antagonized by theophylline. We conclude that (1) intraluminal adenosine and its analogues are effective dilators of intracerebral arterioles, (2) the dilator effects of both intraluminally and extraluminally applied adenosine are predominantly mediated by A2-type receptors, and (3) adenosine receptors mediating vasodilation are not present on the luminal surface of the endothelium.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
5. |
Myocardial Oxygenation in Dogs During Partial and Complete Coronary Artery Occlusion |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 458-464
William Parsons,
Judith Rembert,
Robert Bauman,
Francis Duhaylongsod,
Joseph Greenfield,
Claude Piantadosi,
Preview
|
PDF (1510KB)
|
|
摘要:
Regional myocardial oxygenation was assessed during partial and complete coronary artery occlusion using near infrared spectroscopy. In eight open-chest dogs, partial occlusions resulting in an ≈42% decrease in left anterior descending coronary artery (LAD) blood flow produced an ≈21% decrease in tissue O2stores (tissue oxyhemoglobin plus oxymyoglobin) and no change in the oxidation level of mitochondrial cytochromeaa3. An ≈ 81% reduction in LAD blood flow produced nadir levels of tissue oxyhemoglobin plus oxymyoglobin, maximal levels of deoxyhemoglobin plus deoxymyoglobin, a decline in tissue blood volume, and an ≈39% decrease in cytochromeaa3oxidation level. These changes were associated with an ≈52% decrease from the preischemic baseline in mean transmural myocardial blood flow, measured by radiolabeled microspheres, and an ≈41% decrease in myocardial O2consumption. Complete occlusion resulted in further decreases in myocardial blood flow, O2consumption, tissue blood volume, and cytochromeaa3oxidation state but also produced increases in tissue O2stores to above the nadir levels noted during partial occlusion. These results indicate that decreases in O2delivery during partial coronary occlusion increase O2extraction to sustain mitochondrial O2availability, but as little as a 52% reduction in myocardial blood flow produces maximal O2extraction and depletion of tissue O2stores. Mitochondrial O2availability is restricted further during complete occlusion because of limited O2delivery and, possibly, decreases in tissue blood volume and O2extraction.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
6. |
Modification of Myogenic Intrinsic Tone and [Ca2+]iof Rat Isolated Arterioles by Ryanodine and Cyclopiazonic Acid |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 465-472
Jun Watanabe,
Akihiko Karibe,
Satoru Horiguchi,
Mitsumasa Keitoku,
Shoichi Satoh,
Tamotsu Takishima,
Kunio Shirato,
Preview
|
PDF (3966KB)
|
|
摘要:
The role of the sarcoplasmic reticulum (SR) in regulating myogenic tone and [Ca2+]iwas examined with ryanodine and cyclopiazonic acid (CPA) in the rat skeletal muscle arteriole (Ask) and mesenteric arteriole (Ams). Arterioles were cannulated at both ends to control luminal pressure in a tissue bath. Luminal diameter was measured with a video-monitored microscopic system. Fura 2-AM was loaded to measure [Ca2+]iusing the fluorescence intensity ratio at excitation wavelengths of 340 to 380 nm (F340/380). The myogenic response (luminal pressure was increased from 40 to 100 mm Hg) and the intrinsic tone at 40 mm Hg were observed in Askbut not in Ams. Ryanodine (10−5M) decreased the steady-state diameter of Askfrom 138±8 to 85±9 μm (P<.05) and increased the F340/380 ratio; these effects were reversed by nifedipine or Ca2+-free solution. Ryanodine shifted the [Ca2+]o-contraction response curve upward. CPA (10−5M) also decreased the steady-state diameter of Askfrom 131±7 to 98±11 μm (P<.05). In contrast, Amsresponded to neither ryanodine nor CPA. Caffeine-induced contractions were significantly reduced by either ryanodine or CPA in both arterioles. These results indicate that SR dysfunction increased the susceptibility of the arteriolar tone to [Ca2+]oand enhanced the tone of Ask. In conclusion, the SR function may play a critical role in regulating [Ca2+]iand the intrinsic tone of Askthat was myogenically active at physiological luminal pressure.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
7. |
Immunohistochemical Delineation of the Conduction System IThe Sinoatrial Node |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 473-481
Petra Oosthoek,
Szabolcs Virágh,
Angelique Mayen,
Marjan van Kempen,
Wouter Lamers,
Antoon Moorman,
Preview
|
PDF (13254KB)
|
|
摘要:
We have raised a mouse monoclonal antibody that reacts specifically with the myocytes of the sinoatrial node of the bovine heart. By use of this antibody (445-6E10) and antibodies against the gap junction protein connexin43, the periphery of the sinoatrial node and the distribution of gap junctions in the nodal region were studied. The reaction patterns of 445-6E10 and anti-connexin43 are exactly complementary; ie, connexin43 was not detected in the nodal myocytes but was clearly present in the atrial myocytes. Both reaction patterns demonstrate that nodal myocytes and atrial myocytes can unambiguously be distinguished by their characteristic molecular phenotype. The transitional nodal myocytes at the periphery of the node that have intermediate morphological and electrophysiological characteristics could now clearly be defined as nodal by our immunohistochemical criteria. The center of the node is surrounded by a region of interdigitating nodal and atrial bundles. Nodal bundles, coming from the center of the node, penetrate the atrial myocardium aligned at atrial bundles, forming histological connections between nodal and atrial myocytes at regular distances. This interdigitating arrangement of bundles of connexin43 -negative nodal and connexin43 -positive atrial myocytes is also found in the human and rat heart. We hypothesize that the architecture of the periphery of the node is important to prevent silencing of the pacemaking nodal myocytes by the atrium while ensuring a sufficient source loading of the nodal myocytes.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
8. |
Immunohistochemical Delineation of the Conduction System IIThe Atrioventricular Node and Purkinje Fibers |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 482-491
Petra Oosthoek,
Szabolcs Viráigh,
Wouter Lamers,
Antoon Moorman,
Preview
|
PDF (18063KB)
|
|
摘要:
Using an antibody that reacts specifically with the myocytes of the conduction system of the bovine heart, we have studied the atrioventricular node and the spatial distribution of the Purkinje fibers in the bovine heart. This study was complemented by studying the distribution of the gap junction protein connexin43 in these areas in the bovine heart and in the human heart. The large Purkinje fibers in the bovine heart are arranged in a two-dimensional network underneath the endocardium. At discrete sites, these fibers branch to the Purkinje fibers situated between the muscle bundles of the ventricular mass. These intramural Purkinje fibers are arranged in sheets that form a complex three-dimensional network of lamellas. Contacts with the ventricular myocytes are found throughout the myocardial wall, with the exception of a subepicardial layer of 2-mm thickness, ie, 10% to 15% of the wall thickness. The spatial arrangement of the Purkinje fibers correlates well with data on electrophysiology. Connexin43 was not detected in the myocytes of the atrioventricular node, whereas in the Purkinje fibers of the atrioventricular bundle and of the bundle branches, abundant expression of connexin43 was found in both humans and cows. In the bovine Purkinje fibers, a remarkable subcellular distribution of connexin43 is found: it occupies the entire plasma membrane facing other Purkinje cells but not that facing the surrounding connective tissue. The structural differences in architecture of the ventricular conduction system in humans and cows seems not to result in substantial differences in conduction velocities. However, the Purkinje fiber network in the bovine heart may explain the efficient ventricular excitation, as reflected by the relatively short QRS complex compared with that in the human heart, where intramural Purkinje fibers are not found.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
9. |
ATP‐Dependent Closure and Reactivation of Inward Rectifier K+Channels in Endothelial Cells |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 492-495
S.-P. Olesen,
M. Bundgaard,
Preview
|
PDF (776KB)
|
|
摘要:
This report presents the results of a patch-clamp study examining the role of intracellular ATP in the regulation of endothelial inward rectifier K+channels. Administration of ATP to the cytosolic surface of inside-out patches reversibly activated the K+channel within seconds. ATP (1 mM) increased the mean open probability by a factor of 3.5, primarily by increasing the number of openings. Administration of the nonhydrolyzable ATP analogue ATP-γ-S failed to modulate channel activity. Inhibition of ATP synthesis by administration of cyanide plus iodoacetate resulted in channel closure within 1 to 6 minutes. In experiments in which ATP was coadministered with the metabolic blockers, the channel activity continued unchanged for up to 30 minutes, but when ATP was removed, the activity rapidly decayed. We propose that normal functioning of the inward rectifier K+channel is ATP dependent. Phosphorylation of the channel molecule is probably essential for maintaining activity.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
10. |
Effect of Myocardial Ischemia on Stimulation‐Evoked Noradrenaline Release Modulated Neurotransmission in Rat, Guinea Pig, and Human Cardiac Tissue |
|
Circulation Research,
Volume 73,
Issue 3,
1993,
Page 496-502
Melchior Seyfarth,
Ybai Feng,
Siegfried Hagl,
Fritz Sebening,
Gert Richardt,
Albert Schömig,
Preview
|
PDF (1650KB)
|
|
摘要:
The effect of myocardial ischemia and its major metabolic changes, such as anoxia, acidosis, and hyperkalemia, on exocytotic noradrenaline release was investigated in rat, guinea pig, and human cardiac tissue. Noradrenaline release was evoked by electrical field stimulation, and the effect of each experimental intervention on stimulation-evoked noradrenaline release (S2) was intraindividually compared with the release induced by a control stimulation (S1). In perfused hearts, 10 minutes of global ischemia caused a reduction of noradrenaline overflow in rat hearts (mean S2/S1,0.31), whereas the overflow was increased in guinea pig hearts (S2/S1,1.89). This species-dependent effect may be caused by quantitatively different responses to facilitating and suppressing factors of noradrenaline release in both species. Anoxia and substrate-free perfusion increased noradrenaline overflow in guinea pig hearts (S2/S1, 2.40) but had no significant effect in rat hearts (S2/S1, 0.75). Acidosis (pH 6.0) resulted in a suppression of noradrenaline release in rat hearts (S2/Si, 0.16), whereas it had only a minor inhibiting effect in guinea pig hearts (S2/S1, 0.67). Hyperkalemia had a comparable effect in both species (S2/Sl at 15 mmol/L K+, 1.17 in rat and 1.14 in guinea pig; and S2/Sl at 20 mmol/L K+, 0.64 in rat and 0.41 in guinea pig). To obtain results regarding the modulation of noradrenaline release in human myocardium, human atrial tissue was incubated, and the effect of anoxia, acidosis, and hyperkalemia on stimulation-evoked noradrenaline release was investigated. Anoxia had a moderate facilitating effect on stimulation-evoked noradrenaline release (S2/S1, 1.20), whereas acidosis (S2/S1, 0.35) and hyperkalemia resulted in a suppression (S2/SI at 15 mmol/L K+, 0.63; and S2/Sl at 20 mmol/L K+, 0.03). When the same studies were performed in incubated rat and guinea pig atrial tissue, stimulation-evoked noradrenaline release was modulated by the same metabolic factors as in perfused hearts. In conclusion, stimulation-evoked noradrenaline release in ischemic myocardium is determined by facilitating and suppressing factors in guinea pig, rat, and human cardiac tissue. In human hearts, the suppressing factors dominate even more than in rat hearts, whereas in guinea pig hearts, the facilitating factors outweigh the suppressing factors during early myocardial ischemia.
ISSN:0009-7330
出版商:OVID
年代:1993
数据来源: OVID
|
|