p38 MAP kinase inhibitor reverses stress-induced cardiac myocyte dysfunction

2005 ◽  
Vol 98 (1) ◽  
pp. 77-82 ◽  
Author(s):  
Hong Kan ◽  
Dale Birkle ◽  
Abnash C. Jain ◽  
Conard Failinger ◽  
Sherry Xie ◽  
...  
Keyword(s):  
Map Kinase ◽  
Cardiac Myocyte ◽  
Kinase Inhibitor ◽  
Ventricular Myocytes ◽  
Myocardial Dysfunction ◽  
P38 Map Kinase ◽  
Border Detection ◽  
Rat Ventricular Myocytes ◽  
Adult Rat ◽  
Fractional Shortening

Stress is gaining increasing acceptance as an independent risk factor contributing to adverse cardiovascular outcomes. Potential mechanisms responsible for the deleterious effects of stress on the development and progression of cardiovascular disease remain to be elucidated. An established animal model of stress in humans is the prenatally stressed (PS) rat. We stressed rats in their third trimester of pregnancy by daily injections of saline and moving from cage to cage. Male offspring of these stressed dams (PS) and age-matched male control offspring (control) were further subjected to restraint stress (R) at 6 and 7 wk of age. Echocardiography revealed a significant decrease in fractional shortening in PS + R vs. controls + R (45.8 ± 3.9 vs. 61.9 ± 2.4%, PS + R vs. controls + R; P < 0.01; n = 12). Isolated adult rat ventricular myocytes from PS + R also revealed diminished fractional shortening (6.7 ± 0.8 vs. 12.7 ± 1.1%, PS + R vs. controls + R; P < 0.01; n = 24) and blunted inotropic responses to isoproterenol ( P < 0.01; n = 24) determined by automated border detection. The p38 mitogen-activated protein (MAP) kinase inhibitor SB-203580 blocked p38 MAP kinase phosphorylation, reversed the depression in fractional shortening, and partially ameliorated the blunted adrenergic signaling seen in adult rat ventricular myocytes from PS + R. Phosphorylation of p38 MAP kinase in cardiac myocytes by stress may be sufficient to lead to myocardial dysfunction in animal models and possibly humans.

Differential MAP kinase activation and Na+/H+exchanger phosphorylation by H2O2 in rat cardiac myocytes

2001 ◽  
Vol 281 (5) ◽  
pp. C1542-C1550 ◽  
Author(s):  
Shan Wei ◽  
Emily C. Rothstein ◽  
Larry Fliegel ◽  
Louis J. Dell'Italia ◽  
Pamela A. Lucchesi
Keyword(s):  
Reactive Oxygen Species ◽  
Map Kinase ◽  
Map Kinases ◽  
Cardiac Myocyte ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion ◽  
Oxygen Species ◽  
Rat Ventricular Myocytes ◽  
Adult Rat ◽  
Jnk Activation

Bursts in reactive oxygen species production are important mediators of contractile dysfunction during ischemia-reperfusion injury. Cellular mechanisms that mediate reactive oxygen species-induced changes in cardiac myocyte function have not been fully characterized. In the present study, H2O2 (50 μM) decreased contractility of adult rat ventricular myocytes. H2O2 caused a concentration- and time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein (MAP) kinases in adult rat ventricular myocytes. H2O2(50 μM) caused transient activation of ERK1/2 and p38 MAP kinase that was detected as early as 5 min, was maximal at 20 min (9.6 ± 1.2- and 9.0 ± 1.6-fold, respectively, vs. control), and returned to baseline at 60 min. JNK activation occurred more slowly (1.6 ± 0.2-fold vs. control at 60 min) but was sustained at 3.5 h. The protein kinase C inhibitor chelerythrine completely blocked JNK activation and reduced ERK1/2 and p38 activation. The tyrosine kinase inhibitors genistein and PP-2 blocked JNK, but not ERK1/2 and p38, activation. H2O2-induced Na+/H+ exchanger phosphorylation was blocked by the MAP kinase kinase inhibitor U-0126 (5 μM). These results demonstrate that H2O2-induced activation of MAP kinases may contribute to cardiac myocyte dysfunction during ischemia-reperfusion.

Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture

1999 ◽  
Vol 277 (3) ◽  
pp. H1189-H1199 ◽  
Author(s):  
David J. Pinsky ◽  
Walif Aji ◽  
Matthias Szabolcs ◽  
Eleni S. Athan ◽  
Youping Liu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Ventricular Myocytes ◽  
No Production ◽  
P53 Expression ◽  
Rat Ventricular Myocytes ◽  
Adult Rat

Excessive nitric oxide (NO) production within the heart is implicated in the pathogenesis of myocyte death, but the mechanism whereby NO kills cardiac myocytes is not known. To determine whether NO may trigger programmed cell death (apoptosis) of adult rat ventricular myocytes in culture, the NO donor S-nitroso- N-acetylpenicillamine (SNAP) was shown to kill purified cardiac myocytes in a dose-dependent fashion. In situ analysis of ventricular myocytes plated on chamber slides using nick-end labeling of DNA demonstrated that SNAP induces cardiac myocyte apoptosis, which was confirmed by the identification of oligonucleosomal DNA fragmentation on agarose gel electrophoresis. Similarly, treatment of cardiac myocytes with cytokines that induce inducible NO synthase was shown to cause an NO-dependent induction of apoptosis. Addition of reduced hemoglobin to scavenge NO liberated by SNAP extinguished both the increase in percentage of apoptotic cells and the appearance of DNA ladders. Treatment with SNAP (but not with N-acetylpenicillamine or SNAP + hemoglobin) not only induced apoptosis but resulted in a marked increase in p53 expression in cardiac myocytes detected by Western blotting and immunohistochemistry. These data indicate that NO has the capacity to kill cardiac myocytes by triggering apoptosis and suggest the involvement of p53 in this process.

scholarly journals p38 MAP kinase inhibitor reverses stress-induced myocardial dysfunction in vivo

2009 ◽  
Vol 106 (4) ◽  
pp. 1132-1141 ◽  
Author(s):  
Fangping Chen ◽  
Hong Kan ◽  
Gerry Hobbs ◽  
Mitchell S. Finkel
Keyword(s):  
Map Kinase ◽  
Diastolic Function ◽  
Prenatal Stress ◽  
Intraperitoneal Injection ◽  
Restraint Stress ◽  
Kinase Inhibitor ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
P38 Map Kinase ◽  
Sb 203580

Recent clinical reports strongly support the intriguing possibility that emotional stress alone is sufficient to cause reversible myocardial dysfunction in patients. We previously reported that a combination of prenatal stress followed by restraint stress (PS+R) results in echocardiographic evidence of myocardial dysfunction in anesthetized rats compared with control rats subjected to the same restraint stress (Control+R). We now report results of our catheter-based hemodynamic studies in both anesthetized and freely ambulatory awake rats, comparing PS+R vs. Control+R. Systolic function [positive rate of change in left ventricular pressure over time (+dP/d t)] was significantly depressed ( P < 0.01) in PS+R vs. Control+R both under anesthesia (6,287 ± 252 vs. 7,837 ± 453 mmHg/s) and awake (10,438 ± 741 vs. 12,111 ± 652 mmHg/s). Diastolic function (−dP/d t) was also significantly depressed ( P < 0.05) in PS+R vs. Control+R both under anesthesia (−5,686 ± 340 vs. −7,058 ± 458 mmHg/s) and awake (−8,287 ± 444 vs. 10,440 ± 364 mmHg/s). PS+R also demonstrated a significantly attenuated ( P < 0.05) hemodynamic response to increasing doses of the β-adrenergic agonist isoproterenol. Intraperitoneal injection of the p38 MAP kinase inhibitor SB-203580 reversed the baseline reduction in +dP/d t and −dP/d t as well as the blunted isoproterenol response. Intraperitoneal injection of SB-203580 also reversed p38 MAP kinase and troponin I phosphorylation in cardiac myocytes isolated from PS+R. Thus the combination of prenatal stress followed by restraint stress results in reversible depression in both systolic and diastolic function as well as defective β-adrenergic receptor signaling. Future studies in this animal model may provide insights into the basic mechanisms contributing to reversible myocardial dysfunction in patients with ischemic and nonischemic cardiomyopathies.

scholarly journals Activated macrophages decrease rat cardiac myocyte contractility: importance of ICAM-1-dependent adhesion

1999 ◽  
Vol 277 (1) ◽  
pp. H253-H260 ◽  
Author(s):  
Matthew G. Simms ◽  
Keith R. Walley
Keyword(s):  
Cardiac Myocyte ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Myocardial Dysfunction ◽  
Peritoneal Macrophages ◽  
Intercellular Adhesion Molecule ◽  
Activated Macrophages ◽  
Intercellular Adhesion Molecule 1 ◽  
Tnf Α ◽  
Fractional Shortening

Macrophages are found in the heart as part of the inflammatory response. To determine whether macrophages could contribute to myocardial dysfunction, rat ventricular myocytes were isolated and cocultured with elicited peritoneal macrophages in media containing tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, or endotoxin for 4 h. Cardiac myocytes were electrically stimulated, and fractional shortening was determined using videomicroscopy. When myocytes alone or myocytes in coculture with macrophages separated by a membrane were challenged with TNF-α, lipopolysaccharide, or IL-1, fractional shortening did not decrease. When macrophages were allowed to contact myocytes, fractional shortening decreased from 20.1 ± 0.9% in unchallenged macrophage-myocyte cocultures to 15.5 ± 0.9, 16.3 ± 0.8, and 15.8 ± 0.6% when challenged for 4 h with TNF-α, endotoxin, or IL-1β, respectively ( P < 0.05). Myocytes had a mean adherence of 4.2 ± 0.2 macrophages after TNF-α challenge compared with 2.6 ± 0.3 for controls ( P < 0.05). The number of adherent macrophages was associated with the decrease in fractional shortening. Anti-intercellular adhesion molecule-1 (ICAM-1) reduced macrophage adherence and prevented the decrease in fractional shortening. This decrease was also prevented by desferoxamine, superoxide dismutase, and nitro-l-arginine methyl ester. This suggests that activated macrophages adhere to myocytes via ICAM-1, and adherent macrophages decrease their contractile function via TNF-α, oxygen free radicals, and nitric oxide.

Inhibition of Ca2+ current in neonatal and adult rat ventricular myocytes by the tyrosine kinase inhibitor, genistein

1998 ◽  
Vol 345 (3) ◽  
pp. 309-314 ◽  
Author(s):  
Yasuhiro Katsube ◽  
Hisashi Yokoshiki ◽  
Lam Nguyen ◽  
Masao Yamamoto ◽  
Nicholas Sperelakis
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Ventricular Myocytes ◽  
Rat Ventricular Myocytes ◽  
Adult Rat

Salicylic acid alters endothelin-1 binding in intact adult rat ventricular myocytes

2004 ◽  
Vol 82 (6) ◽  
pp. 728-738 ◽  
Author(s):  
Hala Farhat ◽  
Bruce G Allen
Keyword(s):  
Salicylic Acid ◽  
Map Kinase ◽  
Ventricular Myocytes ◽  
Ventricular Myocyte ◽  
Dependent Manner ◽  
Binding Studies ◽  
Receptor Ligand ◽  
Rat Ventricular Myocytes ◽  
Endothelin 1 ◽  
Adult Rat

Endothelin receptors ETAR and ETBR form tight receptor–ligand complexes that complicate our understanding of the physiological, pharmacological, and biochemical properties of these receptors. Although radioligand–binding studies have demonstrated the binding of endothelin-1 (ET-1) to ETAR to be essentially irreversible, ETAR internalize in a ligand-dependent manner, release ET-1, and then recycle to the cell surface. Salicylic acid (SA) reduces ET-1 binding (IC50 = 10 mmol/L) to recombinant ETAR in isolated membranes by promoting dissociation of [125I]ET-1. In the present study, SA (5 mmol SA/L) did not alter [125I]ET-1 binding to intact adult rat ventricular myocytes. The lack of effect was not due to internalization of receptor–ligand complexes. However, 100 mmol SA/L significantly reduced [125I]ET-1 binding to both intact myocytes and isolated membranes. SA induced the phosphorylation p42/44 extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase and an unidentified 40-kDa protein on the activating threonine-glutamic acid-tyrosine (T-E-Y) motif. ERK phosphorylation was reduced by a MAP kinase kinase (MEK) inhibitor, PD98059. Phosphorylation of p40 was reduced by the p38 MAP kinase inhibitor SB203580, but not PD98059. However, inhibition of ERK or p38 MAP kinases did not alter the ability of 100 mmol SA/L to induce dissociation of [125I]ET-1. These results suggest that, in the ventricular myocyte, salicylic acid alters the kinetics of ET-1 binding. The results also suggest an allosteric binding site may be present that modulates the dissociation of ET-1 receptor–ligand complexes in response to an as-of-yet unidentified mediator.Key words: cell communication, endothelin, endothelin receptor, inotropic agents, signal transduction, heart, ventricular myocyte.

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