Abstract:
:Although isoform-selective translocation of protein kinase C (PKC) epsilon appears to play an important role in the late phase of ischemic preconditioning (PC), the mechanism(s) responsible for such translocation remains unclear. Furthermore, the signaling pathway that leads to the development of late PC after exogenous administration of NO in the absence of ischemia (NO donor-induced late PC) is unknown. In the present study we tested the hypothesis that NO activates PKC and that this is the mechanism for the development of both ischemia-induced and NO donor-induced late PC. A total of 95 chronically instrumented, conscious rabbits were used. In rabbits subjected to ischemic PC (six 4-minute occlusion/4-minute reperfusion cycles), administration of the NO synthase inhibitor Nomega-nitro-L-arginine (group III), at doses previously shown to block the development of late PC, completely blocked the ischemic PC-induced translocation of PKCepsilon but not of PKCeta, indicating that increased formation of NO is an essential mechanism whereby brief ischemia activates the epsilon isoform of PKC. Conversely, a translocation of PKCepsilon and -eta quantitatively similar to that induced by ischemic PC could be reproduced pharmacologically with the administration of 2 structurally unrelated NO donors, diethylenetriamine/NO (DETA/NO) and S-nitroso-N-acetylpenicillamine (SNAP), at doses previously shown to elicit a late PC effect. The particulate fraction of PKCepsilon increased from 35+/-2% of total in the control group (group I) to 60+/-1% after ischemic PC (group II) (P<0.05), to 54+/-2% after SNAP (group IV) (P<0.05) and to 52+/-2% after DETA/NO (group V) (P<0.05). The particulate fraction of PKCeta rose from 66+/-5% in the control group to 86+/-3% after ischemic PC (P<0.05), to 88+/-2% after SNAP (P<0.05) and to 85+/-1% after DETA/NO (P<0.05). Neither ischemic PC nor NO donors had any appreciable effect on the subcellular distribution of PKCalpha, -beta1, -beta2, -gamma, -delta, - micro, or -iota/lambda; on total PKC activity; or on the subcellular distribution of total PKC activity. Thus, the effects of SNAP and DETA/NO on PKC closely resembled those of ischemic PC. The DETA/NO-induced translocation of PKCepsilon (but not that of PKCeta) was completely prevented by the administration of the PKC inhibitor chelerythrine at a dose of 5 mg/kg (group VI) (particulate fraction of PKCepsilon, 38+/-4% of total, P<0.05 versus group V; particulate fraction of PKCeta, 79+/-2% of total). The same dose of chelerythrine completely prevented the DETA/NO-induced late PC effect against both myocardial stunning (groups VII through X) and myocardial infarction (groups XI through XV), indicating that NO donors induce late PC by activating PKC and that among the 10 isozymes of PKC expressed in the rabbit heart, the epsilon isotype is specifically involved in the development of this form of pharmacological PC. In all groups examined (groups I through VI), the changes in the subcellular distribution of PKCepsilon protein were associated with parallel changes in PKCepsilon isoform-selective activity, whereas total PKC activity was not significantly altered. Taken together, the results provide direct evidence that isoform-selective activation of PKCepsilon is a critical step in the signaling pathway whereby NO initiates the development of a late PC effect both after an ischemic stimulus (endogenous NO) and after treatment with NO-releasing agents (exogenous NO). To our knowledge, this is also the first report that NO can activate PKC in the heart. The finding that NO can promote isoform-specific activation of PKC identifies a new biological function of this radical and a new mechanism in the signaling cascade of ischemic PC and may also have important implications for other pathophysiological conditions in which NO is involved and for nitrate therapy.
journal_name
Circ Resjournal_title
Circulation researchauthors
Ping P,Takano H,Zhang J,Tang XL,Qiu Y,Li RC,Banerjee S,Dawn B,Balafonova Z,Bolli Rdoi
10.1161/01.res.84.5.587subject
Has Abstractpub_date
1999-03-19 00:00:00pages
587-604issue
5eissn
0009-7330issn
1524-4571journal_volume
84pub_type
杂志文章abstract::Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and cardiac-specific metabolism that occur across a spectrum of cardiovascular disease states. Findings from metabolomics studi...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.117.311002
更新日期:2018-04-27 00:00:00
abstract::The study was performed to determine whether there is a structural vascular abnormality in normotensive subjects with hypertensive relatives. We examined maximal vasodilator capacity of forearm resistance vessels in 23 normotensive young men (mean blood pressure 94 +/- 0.4 mm Hg, mean +/- SE) with hypertensive relativ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.50.5.671
更新日期:1982-05-01 00:00:00
abstract::Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been sho...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.172619
更新日期:2008-08-15 00:00:00
abstract::This study investigated the possible roles of strongly binding myosin crossbridges in determining loaded shortening and power output in cardiac myocytes. Single skinned cardiac myocytes were attached between a force transducer and position motor, and shortening velocities were measured over a range of loads during var...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.87.9.768
更新日期:2000-10-27 00:00:00
abstract::Gene transfer to blood vessels is a promising new approach to the treatment of the vascular diseases, but the feasibility of gene transfer to adult human vessels has not been explored. We introduced an adenovirus vector encoding a marker gene human placental alkaline phosphatase into normal and atherosclerotic human v...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.82.12.1243
更新日期:1998-06-29 00:00:00
abstract:RATIONALE:Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies ha...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.112.270132
更新日期:2012-09-28 00:00:00
abstract::The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and high incidence of sudden death, despite causing little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular hypertrophy...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000059562.91384.1A
更新日期:2003-03-07 00:00:00
abstract::To investigate the contributions of humoral and hemodynamic factors to cardiac adaptations associated with chronic exercise, female Fischer 344 rats were subjected to chronic swimming, infrarenal cardiac transplantation, or both. Swimming resulted in hypertrophy (11-12%) of the in situ hearts in both the unoperated an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.67.3.780
更新日期:1990-09-01 00:00:00
abstract:RATIONALE:Smooth muscle precursor cells have previously been reported to reside in bone marrow and in the circulation, but little is currently known regarding the proximate stimuli for smooth muscle cell differentiation of these putative progenitors. OBJECTIVE:Because local thrombin generation occurs as an initial res...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.199984
更新日期:2009-07-31 00:00:00
abstract:RATIONALE:Myofibroblasts are believed to evolve from precursor cells; however, whether noncardiomyocyte cardiac cells (NMCCs; ie, endothelial cells, smooth muscle cells, pericytes, and fibroblasts) that have been derived from human-induced pluripotent stem cells (hiPSCs) can transdifferentiate into myofibroblast-like c...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.118.313094
更新日期:2018-12-07 00:00:00
abstract::The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate was used to probe the role of protein kinase-C in the modulation of alpha-adrenergic receptor-coupled calcium efflux in cultured vascular smooth muscle cells derived from rabbit aorta. Exposure of cells to 12-O-tetradecanoyl phorbol-13-acetate for 6 minutes cause...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.58.3.393
更新日期:1986-03-01 00:00:00
abstract::Alveolar epithelial beta-adrenergic receptor (betaAR) activation accelerates active Na+ transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechani...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000125623.56442.20
更新日期:2004-04-30 00:00:00
abstract::Heptanol blocks sodium current (INa) in nerve, but its effects on cardiac INa have not been well characterized. Block of INa by heptanol was studied in 16 internally perfused voltage-clamped cardiac Purkinje cells at reduced Na+ (45 mM outside, 0 mM inside). Heptanol block of peak sodium conductance was well described...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.4.977
更新日期:1991-04-01 00:00:00
abstract::The effect of hypercapnia on coronary vascular resistance (CVR) was studied in seven open-chest dogs. Coronary blood flow was supplied to the cannulated left main coronary artery from the femoral artery by a precision pump. Coronary arterial PCO2 was locally controlled with a small membrane oxygenator in the coronary ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.39.4.558
更新日期:1976-10-01 00:00:00
abstract::Hemodynamics play an important role in cardiovascular development, and changes in blood flow can cause congenital heart malformations. The endothelium and endocardium are subjected to mechanical forces, of which fluid shear stress is correlated to blood flow velocity. The shear stress responsive genes lung Krüppel-lik...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000171901.40952.0d
更新日期:2005-06-24 00:00:00
abstract::We report the hemodynamic parameters of stage 18, 21, 24, and 27 chick embryos (from 3 to 5 days of incubation). Dorsal aortic blood velocity and mean vitelline artery blood pressure are measured with a 20 MHz pulsed-Doppler meter and servo-null pressure system respectively. We also measure heart rate, dorsal aortic d...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.51.6.810
更新日期:1982-12-01 00:00:00
abstract:RATIONALE:Natural killer (NK) cells are lymphocytes of the innate immune system that play specialized and niche-specific roles in distinct organs. OBJECTIVE:We investigated the possible function of NK cells in the pathogenesis of congestive heart failure after myocardial infarction. METHODS AND RESULTS:Depletion of N...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.302625
更新日期:2014-02-14 00:00:00
abstract::The precise, temporal order of gene expression during development is critical to ensure proper lineage commitment, cell fate determination, and ultimately, organogenesis. Epigenetic regulation of chromatin structure is fundamental to the activation or repression of genes during embryonic development. In recent years, ...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.115.301517
更新日期:2014-07-07 00:00:00
abstract::The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprote...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.4.585
更新日期:1997-10-01 00:00:00
abstract::We examined whether albumin-derived advanced glycosylation end products (AGEs) downregulate the expression of endothelial nitric oxide synthase (NOS). Significant reductions in NOS activity and cGMP levels in bovine aortic endothelial cells were observed when exposed to different concentrations of albumin-derived AGEs...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.3.e50
更新日期:2000-02-18 00:00:00
abstract::The contribution of centrally originating sympathetic activity to the myocardial extracellular accumulation of noradrenaline during the early phase of ischemia has been assessed in a perfused (Langendorff) rat heart preparation isolated except for its sympathetic innervation. A 10-minute electrical stimulation (4 Hz, ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.55.5.702
更新日期:1984-11-01 00:00:00
abstract::This report evaluates pulse wave propagation with respect to contributions by vascular wall elastic and geometric properties, vessel wall and blood viscosity, and nonlinearities in system parameters and in the equations of motion. Discrepancies in results obtained with different experimental methods and theory are dis...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.49.2.442
更新日期:1981-08-01 00:00:00
abstract::We performed morphological studies of myocardial contracture to define its nature and relationship to mechanical changes occurring during metabolic blockade. Isolated rat papillary and trabecular muscles were stretched to the apices of their length-tension curves and stimulated to contract isometrically 12 times a min...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.45.2.298
更新日期:1979-08-01 00:00:00
abstract::Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.0000046452.67724.b8
更新日期:2002-12-13 00:00:00
abstract::The effects of synthetic human atrial 28-amino acid peptide (alpha-human atrial polypeptide) on systemic and renal hemodynamics were examined in two separate groups of Inactin-anesthetized rats. First, mean arterial pressure, heart rate, and cardiac output were measured before and during infusion of the peptide at rat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.57.4.634
更新日期:1985-10-01 00:00:00
abstract::Genome-wide association studies have provided a rich collection of ≈ 58 coronary artery disease (CAD) loci that suggest the existence of previously unsuspected new biology relevant to atherosclerosis. However, these studies only identify genomic loci associated with CAD, and many questions remain even after a genomic ...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.115.306464
更新日期:2016-02-19 00:00:00
abstract::Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, HFpEF is now as common as heart failure with reduced ejection fraction. We now have many successful treatments for heart failure with reduced ejection fraction, while specific treatment op...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.115.302929
更新日期:2014-06-20 00:00:00
abstract::The release of acetylcholine from autonomic nerves in those tissues that receive a cholinergic innervation is widely believed to dilate blood vessels. Exogenously administered acetylcholine in vivo does dilate vascular beds and produce hypotension; however, this latter effect is indirect and probably the result of lib...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.65.2.237
更新日期:1989-08-01 00:00:00
abstract::Mechanoreceptors and chemoreceptors have been identified inside the kidney, but their functional role is still largely unclear. The aim of this study was to investigate whether changes in urine output could modify the discharge rate of renal afferent fibers. Experiments were performed in anesthetized cats in which aff...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.73.5.906
更新日期:1993-11-01 00:00:00
abstract::The functional disturbance of microvasculature is recognized as an initiating mechanism that underlies the development of various diabetic complications. Although a causal relationship between microvascular leakage and tissue damage has been well documented in diabetic kidneys and eyes, there is a lack of information ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.87.5.412
更新日期:2000-09-01 00:00:00