Endogenous estrogen mediates a higher threshold for endotoxin-induced myocardial protection in females

2006 ◽  
Vol 290 (1) ◽  
pp. R27-R33 ◽  
Author(s):  
Jeffrey M. Pitcher ◽  
Meijing Wang ◽  
Ben M. Tsai ◽  
Ajay Kher ◽  
Nicholas T. Nelson ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Myocardial Protection ◽  
Myocardial Function ◽  
Endotoxin Tolerance ◽  
Left Ventricular ◽  
Female Rats ◽  
Tnf Α ◽  
Endogenous Estrogen ◽  
Developed Pressure ◽  
Jnk Activation

Myocardial endotoxin tolerance may be induced in both males and females; however, it remains unknown whether there are mechanistic and threshold differences between the sexes. We hypothesized that endogenous estrogen mediates a higher threshold for endotoxin (ETX)-induced protection in females. Adult proestrus and ovariectomized (OVX) female rats were preconditioned (PC) with intraperitoneal injections of 125 (PC+125) or 500 (PC+500) μg/kg Salmonella typhimurium LPS (ETX) or normal saline (PC−). Twenty-four hours later, injury dose ETX (500 μg/kg) was injected. After 6 h, myocardial function was measured via Langendorff. p38 MAPK and JNK activation and TNF-α, IL-1, and IL-6 expression were evaluated. ETX injury significantly decreased left ventricular developed pressure in PC− groups vs. controls. PC+500 regimen protected against ETX injury, resulting in normal cardiac function. PC+125 regimen protected OVX but not proestrus females, which had diminished myocardial function. Activated JNK and TNF-α increased in PC− but were diminished in PC+500 animals. Importantly, activated JNK and TNF increased in PC+125 proestrus females, whereas PC+125 OVX females displayed decreases in these molecules. There were no differences in p38 MAPK activation or expression of IL-1 or IL-6. These results demonstrate that proestrus females require a higher stimulus (PC+500) to achieve myocardial protection against ETX injury. Removal of endogenous estrogen (OVX) lowered the preconditioning threshold (PC+125), resulting in protection after lesser injury. Additionally, myocardial JNK and TNF expression was decreased in OVX PC+125 females, which correlated with myocardial function differences. Therefore, we conclude that endogenous estrogen mediates a higher threshold for ETX tolerance in female myocardium.

Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury

2005 ◽  
Vol 288 (2) ◽  
pp. E321-E326 ◽  
Author(s):  
Meijing Wang ◽  
Lauren Baker ◽  
Ben M. Tsai ◽  
Kirstan K. Meldrum ◽  
Daniel R. Meldrum
Keyword(s):  
Sex Differences ◽  
Inflammatory Response ◽  
P38 Mapk ◽  
Myocardial Function ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Left Ventricular ◽  
Rt Pcr ◽  
Tnf Α

The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-α, IL-1β, and IL-6 (RT-PCR, ELISA); IL-1α and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/d t) and negative (−dP/d t) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-α, IL-1β, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.

scholarly journals Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1β

2007 ◽  
Vol 292 (4) ◽  
pp. H1694-H1699 ◽  
Author(s):  
Meijing Wang ◽  
Troy Markel ◽  
Paul Crisostomo ◽  
Christine Herring ◽  
Kirstan K. Meldrum ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Myocardial Function ◽  
Tissue Injury ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Cytokine Signaling ◽  
Myocardial Inflammation ◽  
Socs Proteins ◽  
Developed Pressure ◽  
Factor Α

Tumor necrosis factor-α (TNF-α) plays an important role in the development of heart failure. There is a direct correlation between myocardial function and myocardial TNF levels in humans. TNF may induce local inflammation to exert tissue injury. On the other hand, suppressors of cytokine signaling (SOCS) proteins have been shown to inhibit proinflammatory signaling. However, it is unknown whether TNF mediates myocardial inflammation via STAT3/SOCS3 signaling in the heart and, if so, whether this effect is through the type 1 55-kDa TNF receptor (TNFR1). We hypothesized that TNFR1 deficiency protects myocardial function and decreases myocardial IL-6 production via the STAT3/SOCS3 pathway in response to TNF. Isolated male mouse hearts ( n = 4/group) from wild-type (WT) and TNFR1 knockout (TNFR1KO) were subjected to direct TNF infusion (500 pg·ml−1·min−1 × 30 min) while left ventricular developed pressure and maximal positive and negative values of the first derivative of pressure were continuously recorded. Heart tissue was analyzed for active forms of STAT3, p38, SOCS3 and SOCS1 (Western blot analysis), as well as IL-1β and IL-6 (ELISA). Coronary effluent was analyzed for lactate dehydrogenase (LDH) activity. As a result, TNFR1KO had significantly better myocardial function, less myocardial LDH release, and greater expression of SOCS3 (percentage of SOCS3/GAPDH: 45 ± 4.5% vs. WT 22 ± 6.5%) after TNF infusion. TNFR1 deficiency decreased STAT3 activation (percentage of phospho-STAT3/STAT3: 29 ± 6.4% vs. WT 45 ± 8.8%). IL-6 was decreased in TNFR1KO (150.2 ± 3.65 pg/mg protein) versus WT (211.4 ± 26.08) mice. TNFR1 deficiency did not change expression of p38 and IL-1β following TNF infusion. These results suggest that deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1β.

The role of K+ATP channels in the control of pre- and post-ischemic left ventricular developed pressure in septic rat hearts

2001 ◽  
Vol 79 (3) ◽  
pp. 213-219 ◽  
Author(s):  
Jitka A Ismail ◽  
Kathleen H McDonough
Keyword(s):  
Coronary Flow ◽  
Myocardial Protection ◽  
Myocardial Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Lv Function ◽  
Rat Hearts ◽  
Developed Pressure ◽  
Septic Group

Myocardial function is impaired 24 h after the induction of sepsis, however, recovery of left ventricular (LV) function after 35 min of global ischemia is complete. The mechanisms by which this protection occurs are unknown. Ischemic preconditioning, another form of myocardial protection from ischemia/reperfusion (I/R) injury, has been shown to be modulated by ATP-sensitive potassium (K+ATP) channels. To investigate the role of K+ATP channels in the regulation of coronary flow (CF) and protection from I/R injury in septic rat hearts, we assessed the effects of the K+ATP channel antagonist glibenclamide (GLIB) and the agonist cromakalim (CROM) on pre- and post-ischemic CF and left ventricular developed pressure (LVDP). Although GLIB decreased pre-ischemic CF in both control and septic rat hearts, LVDP was unaffected. After I/R, CF was decreased in GLIB-treated control and septic rat hearts and LVDP was more severely depressed in control rat hearts than in septic rat hearts. CROM increased pre-ischemic CF in the septic group although LVDP was unaltered in both groups. After I/R, control rat heart CF was depressed but LVDP completely recovered. Post-ischemic CF in septic rat hearts was elevated compared with vehicle-treated septic rat hearts, but the recovery of LVDP was not improved. These results suggest that K+ATP channels modulate CF in septic rat hearts, but do not mediate cardioprotection as observed in control rat hearts.Key words: K+ATP channel, preconditioning, ischemia, reperfusion, sepsis.

Oxygen delivery and myocardial function in rabbit hearts perfused with cell-free hemoglobin

1992 ◽  
Vol 72 (2) ◽  
pp. 476-483 ◽  
Author(s):  
V. W. MacDonald ◽  
R. M. Winslow
Keyword(s):  
Oxygen Uptake ◽  
Myocardial Function ◽  
Oxygen Affinity ◽  
Left Ventricular ◽  
Rate Of Change ◽  
Free Hemoglobin ◽  
Langendorff Preparation ◽  
Oxygen Gradients ◽  
Developed Pressure ◽  
Krebs Henseleit Buffer

Isolated rabbit hearts were perfused with Krebs-Henseleit buffer that contained 1.5 g/dl hemoglobin Ao [HbAo; PO2 at which half-saturation of hemoglobin occurs = 12 Torr], human hemoglobin cross-linked between alpha-chains with bis(3,5-dibromosalicyl)fumarate (alpha alpha-Hb; PO2 at which half-saturation of hemoglobin occurs = 30 Torr), or fatty acid-free bovine serum albumin (BSA). Myocardial performance and oxygen uptake were determined at different aortic PO2's [arterial PO2 (PaO2)] by use of an isovolumic Langendorff preparation. Function and oxygen uptake were comparable among the three different groups of hearts at an average mean PaO2 of 557 Torr. As PaO2 decreased, myocardial function was preserved better in hearts perfused with hemoglobin than in hearts perfused with Krebs-Henseleit buffer alone or with BSA. Hearts perfused with either HbAo or alpha alpha-Hb exhibited similar 10% decreases in left ventricular developed pressure and rate of change in left ventricular developed pressure at PaO2 of 141 Torr compared with a 58% decrease with BSA. However, corresponding venous PO2's were lower with HbAo (20 Torr) than with alpha alpha-Hb (35 Torr), and oxygen uptake decreased by 36% with HbAo but remained constant with alpha alpha-Hb. These data suggest that although myocardial function can be sustained over a fairly broad range of hemoglobin oxygen affinities, tissue oxygen gradients and myocardial oxygen uptake are maintained better by cell-free hemoglobin with an oxygen affinity in the normal physiological range.

scholarly journals Effect of dobutamine on intrinsic myocardial function and myocardial apoptosis in septic rats with myocardial dysfunction

2020 ◽  
Author(s):  
Xiang-Xu Tang ◽  
Ya-Qian Xu ◽  
Xiao-Meng Dai ◽  
Yun Xing ◽  
Duo-Meng Yang ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Myocardial Function ◽  
Myocardial Dysfunction ◽  
Cecal Ligation ◽  
Left Ventricular ◽  
Cardiomyocyte Apoptosis ◽  
Fatty Acid Binding ◽  
Myocardial Apoptosis ◽  
Tnf Α

Abstract Background Dobutamine (DOB) has been recommended as the first-line inotrope for septic patients with low cardiac output, but its long-term impact on intrinsic myocardial dysfunction during sepsis remains unclear. This study investigated the long-term effect of DOB on intrinsic myocardial function and cardiomyocyte apoptosis in sepsis. Methods Male Sprague-Dawley rats were randomly divided into sham and cecal ligation and puncture (CLP) groups. The intrinsic myocardial function and other organ functions were measured at different time points, the inflammatory response and serum biomarkers of myocardial injury were also determined. In separate experiments, the effect of DOB (5 or 10 µg/kg) treatment on survival, intrinsic myocardial function, serum and myocardial cytokines and myocardial apoptosis were measured in septic rats. Results The mortality rate of septic rats was 70% on day 10 after CLP. At 6 h after CLP, the left ventricular ± dP/dt were significantly depressed, serum tumor necrosis factor (TNF) –α level, cardiac TNF-α, intercellular adhesion molecule and vascular cell adhesion molecule-1 (VCAM-1) mRNA, and VCAM-1 protein levels were increased, but not serum cTnI, N-terminal pro-brain natriuretic peptide (NT-proBNP), heart-type fatty acid-binding protein (H-FABP), creatinine and urea nitrogen concentrations as well as lung wet-dry weight ratios in CLP group compared with those in sham group. At 9 h after CLP, serum alanine aminotransferase and aspartate aminotransferase activities were higher in CLP rats than controls. At 6 h after CLP, treatment with DOB did not affect the left ventricular ± dP/dt, the levels of TNF-α, interleukin (IL) − 1β and IL-6 in the serum and myocardium as well as cardiomyocyte apoptosis at 20 h after CLP. However, administration of 10.0 µg/kg DOB at 6 h after CLP significantly increased serum IL-10 level and improved survival in septic rats. Conclusions The intrinsic myocardial depression occurs earlier than hepatic and renal dysfunction in severe sepsis and serum cTnI, NT-proBNP and H-FABP are not suitable as an early biomarker for this kind of cardiac dysfunction. For septic rats, DOB treatment in the presence of intrinsic myocardial dysfunction neither improves myocardial function nor attenuates myocardial inflammation and cardiomyocyte apoptosis at the later stage of sepsis.

Myocardial protection from ischemic arrest: potassium and verapamil cardioplegia

1981 ◽  
Vol 240 (3) ◽  
pp. H326-H335 ◽  
Author(s):  
W. W. Pinsky ◽  
R. M. Lewis ◽  
J. B. McMillin-Wood ◽  
H. Hara ◽  
C. J. Hartley ◽  
...  
Keyword(s):  
Calcium Transport ◽  
Myocardial Protection ◽  
Myocardial Function ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
The Other ◽  
Myocardial Segment ◽  
Intracoronary Infusion ◽  
Hemodynamic Function ◽  
And Function

Prolonged normothermic myocardial ischemic arrest results in myocardial dysfunction. This study has investigated the technique of preserving myocardial function by a single bolus intracoronary infusion of combination potassium and verapamil at the onset of ischemic arrest. Sixty-one dogs underwent cardiopulmonary bypass with 60 min of ischemic arrest: 25 received no myocardial protection, 12 received a single intracoronary bolus of KCl, 12 received combination verapamil and KCl, and 12 received verapamil alone. Following the ischemic arrest, hearts protected by combination of potassium and verapamil demonstrated better survival evidenced by the ability of all 12 dogs to resume normal hemodynamic function. The hemodynamic function in the combination potassium and verapamil group also demonstrated better cardiac output, left ventricular dF/dt, and myocardial segment shortening than survivors in the other groups. Subsarcolemmal (SSL) and intermyofibrillar IMF) mitochondria were isolated from these hearts and function evaluated. NADH-linked oxygen consumption was impaired as was calcium transport in the SSL from unprotected ischemic hearts. Intermyofibrillar mitochondria were not different from control or sham. The hearts protected by verapamil and potassium demonstrated normal mitochondrial function.

Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion

2005 ◽  
Vol 288 (1) ◽  
pp. H221-H226 ◽  
Author(s):  
Meijing Wang ◽  
Ben M. Tsai ◽  
Ajay Kher ◽  
Lauren B. Baker ◽  
G. Mathenge Wairiuko ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Functional Recovery ◽  
Caspase 3 ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Caspase 1 ◽  
Tnf Α

Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-α, IL-1β, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-α, IL-1β, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.

p38 MAPK Inhibition Decreases TNF-α Production and Enhances Postischemic Human Myocardial Function

1999 ◽  
Vol 83 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Brian S. Cain ◽  
Daniel R. Meldrum ◽  
Xianzhong Meng ◽  
Charles A. Dinarello ◽  
Brian D. Shames ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Myocardial Function ◽  
Tnf Α

Deleterious effect of ouabain on myocardial function during hypoxia

1989 ◽  
Vol 256 (3) ◽  
pp. H681-H687
Author(s):  
M. J. Cunningham ◽  
C. S. Apstein ◽  
E. O. Weinberg ◽  
B. H. Lorell
Keyword(s):  
Myocardial Function ◽  
Diastolic Pressure ◽  
Lactate Production ◽  
Treated Group ◽  
Left Ventricular ◽  
Ventricular Performance ◽  
Fiber Tension ◽  
Coronary Vasodilatation ◽  
Developed Pressure ◽  
Ventricular Distensibility

The effect of cardiac glycosides on myocardial function during hypoxia is controversial. Accordingly, we studied left ventricular performance during hypoxia and reoxygenation in the presence of a mildly inotropic, nontoxic dose of ouabain using isolated, isovolumic, buffer-perfused rabbit hearts. After 15 min of hypoxia, left ventricular developed pressure was less in the ouabain-treated group than in controls (35 +/- 4 vs. 55 +/- 3 mmHg, P less than 0.025). Left ventricular end-diastolic pressure (LVEDP) increased more during hypoxia in the presence of ouabain (9 +/- 1 to 32 +/- 7 with ouabain vs. 9 +/- 1 to 14 +/- 3 mmHg without ouabain, P less than 0.005) despite comparable degrees of coronary vasodilatation and myocardial lactate production in the two groups. When coronary flow was abruptly reduced to zero to eliminate the coronary turgor contribution to diastolic pressure, LVEDP after 15 min of hypoxia in the presence of ouabain was greater than that in control hearts that did not receive ouabain (13 +/- 4 vs. 4 +/- 1 mmHg, P less than 0.05), implicating greater diastolic myocardial fiber tension in the ouabain group during hypoxia. With reoxygenation, recovery of developed pressure was less and end-diastolic pressure remained elevated in the ouabain-treated group when compared with controls. We conclude that a modestly inotropic dose of ouabain exacerbates the decrease in diastolic ventricular distensibility induced by hypoxia, worsens the decline in developed pressure during hypoxia, and impairs recovery during reoxygenation.

Endotoxin induces cardiac HSP70 and resistance to endotoxemic myocardial depression in rats

1996 ◽  
Vol 271 (4) ◽  
pp. C1316-C1324 ◽  
Author(s):  
X. Meng ◽  
J. M. Brown ◽  
L. Ao ◽  
S. K. Nordeen ◽  
W. Franklin ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein 70 ◽  
Myocardial Function ◽  
Contractile Function ◽  
Left Ventricular ◽  
Saline Control ◽  
Myocardial Depression ◽  
Single Exposure ◽  
Myocardial Contractile ◽  
Developed Pressure

Endotoxin (bacterial lipopolysaccharide, LPS) depresses myocardial function. However, heat shock and sublethal LPS can confer cardiac resistance to postischemic dysfunction. We hypothesized that a prior exposure to LPS stress induces the expression of cardiac heat shock protein 70 (HSP70) and resistance to endotoxemic myocardial depression. Moreover, induction of HSP70 by hyperthermia should also increase cardiac resistance to LPS toxicity. LPS (500 micrograms/kg ip) depressed rat left ventricular developed pressure (LVDP) maximally at 6 h (58.4 +/- 3.72 vs. 101 +/- 1.46 mmHg in saline control, P < 0.01), and myocardial contractile function recovered at 24 h. In rats pretreated with LPS 24 h earlier, subsequent LPS exposure did not depress LVDP (97.0 +/- 3.53 mmHg at 6 h, P < 0.01 vs. single exposure). Both LPS and hyperthermia (42 degrees C, 15 min) induced HSP72 mainly in the cardiac interstitial cells, including macrophages at 24 h after treatment. When hyperthermia-pretreated animals were similarly challenged with LPS, myocardial depression at 6 h was partially abrogated (LVDP 80.1 +/- 5.67 vs. 62.2 +/- 4.91 mmHg in sham+LPS group, P < 0.01). We conclude that LPS induces HSP70 in rat heart and that an exposure to LPS or heat stress confers cardiac resistance to endotoxemic myocardial depression.

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