HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 288/1/H221    most recent 00784.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (32) Citing Articles via Google Scholar Google Scholar Articles by Wang, M. Articles by Meldrum, D. R. Search for Related Content PubMed PubMed Citation Articles by Wang, M. Articles by Meldrum, D. R.

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

Departments of ¹Surgery and ³Cellular and Integrative Physiology and ²Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 3 August 2004 ; accepted in final form 14 September 2004

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
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-, IL-1, 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-, IL-1, 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.

myocardial infarction; sex hormones; inflammation; caspase cascades

Myocardial inflammation may play a crucial role in I/R-induced myocardial dysfunction and the associated loss of cardiomyocytes. The myocardium itself generates inflammatory cytokines, such as TNF- and IL-1, in response to acute I/R, and these locally produced inflammatory mediators contribute to postischemic myocardial functional depression as well as cardiomyocyte apoptosis. One of the signaling enzymes involved in both inflammatory cytokine production and myocyte apoptosis is p38 MAPK. I/R injury results in activation of myocardial p38 MAPK (6, 18, 31), whereas p38 MAPK inhibition leads to improved myocardial function after I/R (17, 23). However, it is unknown whether testosterone affects myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial recovery after acute ischemic injury. On the basis of the results of several recent papers in the trauma literature (29, 30), we hypothesized that testosterone may exert deleterious effects on these processes. The purposes of this study were to investigate the effect of testosterone depletion (castration) or testosterone receptor blockade (flutamide) on postischemic 1) myocardial function, 2) proinflammatory cytokine (TNF-, IL-1, and IL-6) production and p38 MAPK activation, and 3) pro- and antiapoptotic signaling.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Animals. Normal male Sprague-Dawley rats (280–300 g, 9–10 wk; Harlan, Indianapolis, IN) were fed a standard diet and acclimated in a quiet quarantine room for 2 wk before the experiments. The animal protocol was reviewed and approved by the Institutional Animal Care and Use Committee of Indiana University. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, revised 1985).

Experimental groups. Rats were divided into three experimental groups: normal males (n = 12), castrated males (n = 8; castration occurred when the animals weighed 100 g), and males treated with the testosterone receptor blocker (TRB) flutamide (n = 9). Male rats (100–125 g, 5–6 wk) received bilateral castration and were allowed at least 4 wk of recovery. Subcutaneous implantation of 21-day-release pellets containing 10 mg of flutamide was performed in normal male rats (animals were utilized at the end of the 21-day blockade). Isolated rat hearts in all groups were subjected to the same I/R protocol: 15-min equilibration period, 25 min of global ischemia (37°C), and 40 min of reperfusion.

Isolated heart preparation (Langendorff). Rats were anesthetized (pentobarbital sodium, 60 mg/kg ip) and heparinized (500 U ip), and hearts were rapidly excised via median sternotomy and placed in 4°C Krebs-Henseleit solution. The aorta was cannulated, and the heart was perfused (70 mmHg) with oxygenated (95% O₂-5% CO₂) Krebs-Henseleit solution (37°C). A three-way stopcock above the aortic root was used to create global ischemia, during which the heart was placed in a 37°C degassed organ bath. Coronary flow was measured by collecting pulmonary artery effluent. Data were continuously recorded with a PowerLab 8 preamplifier/digitizer (AD Instruments, Milford, MA) and an Apple G4 PowerPC computer (Apple Computer, Cupertino, CA). The maximal positive and negative values of the first derivative of pressure (+dP/dt and –dP/dt) were calculated with PowerLab software.

Myocardial TNF-, IL-1, and IL-6. Heart tissue was homogenized in cold buffer containing (in mM) 20 Tris (pH 7.5), 150 NaCl, 1 EDTA, 1 EGTA, 2.5 sodium pyrophosphate, 1 -glycerophosphate, 1 Na₃VO₄, and 1 PMSF with 1 µg/ml leupeptin and 1% Triton X-100 and centrifuged at 12,000 rpm for 5 min. Myocardial TNF-, IL-1, and IL-6 in the cardiac tissue were determined by ELISA with a commercially available ELISA kit (BD Biosciences, San Diego, CA, and R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. All samples and standards were measured in duplicate.

Western blotting. Western blot analysis was performed to measure p38 MAPK and apoptosis-related proteins. Heart tissue was homogenized in cold buffer containing (in mM) 20 Tris (pH 7.5), 150 NaCl, 1 EDTA, 1 EGTA, 2.5 sodium pyrophosphate, 1 -glycerophosphate, 1 Na₃VO₄, and 1 PMSF with 1 µg/ml leupeptin and 1% Triton X-100 and centrifuged at 12,000 rpm for 5 min. The protein extracts (30 µg/lane) were subjected to electrophoresis on a 12% Tris·HCl gel from Bio-Rad and transferred to a nitrocellulose membrane, which was stained with naphthol blue black to confirm equal protein loading. The membranes were incubated in 5% dry milk for 1 h and then incubated with the following primary antibodies: p38 MAPK antibody, phosphor-p38 MAPK (Thr180/Tyr182) antibody (Cell Signaling Technology, Beverly, MA); caspase-3 (H-277) antibody, caspase-1 p20 (G-19) antibody, caspase-11 (M-20) antibody (Santa Cruz Biotechnology, Santa Cruz, CA); Bcl-2 (Ab-4) antibody (Oncogene Research Products, San Diego, CA), followed by incubation with horseradish peroxidase-conjugated goat anti-rabbit, donkey anti-goat, or goat anti-mouse IgG secondary antibody and detection with SuperSignal West Pico stable peroxide solution (Pierce, Rockford, IL). Films were scanned with an Epson Perfection 3200 Scanner (Epson America, Long Beach, CA), and band density was analyzed with ImageJ software (National Institutes of Health). Spots of dirty background were digitally erased.

Presentation of data and statistical analysis. All reported values are means ± SE (n = 8–12/group). Data were compared with two-way ANOVA with post hoc Bonferroni test or Student's t-test. A two-tailed probability value of <0.05 was considered statistically significant. Representative gels are shown in Figs. 2, 4, and 5 with all lanes/samples from the same gel.

View larger version (24K): [in this window] [in a new window]   Fig. 2. I/R-induced myocardial p38 MAPK phosphorylation. Expression of activated p38 MAPK signaling was increased after I/R injury in normal male hearts relative to castrated males and males treated with TRB. Shown are representative immunoblots. Top: total p38 MAPK. bottom: phosphorylated (p; activated) form of p38 MAPK. All samples were on the same membrane.

View larger version (31K): [in this window] [in a new window]   Fig. 4. Myocardial expression of caspase-1 and caspase-11 in rat hearts of normal males, castrated males, and males treated with TRB after I/R. A: representative immunoblots. Caspase-1 and caspase-11 subunit levels were increased after I/R in hearts of normal males relative to castrated males or males treated with TRB. B: caspase-1 levels represented as % of procaspase-1 levels in untreated males, castrated males, and males treated with TRB. Results are means ± SE. *P < 0.05 vs. untreated male. All samples were on the same membrane.

View larger version (41K): [in this window] [in a new window]   Fig. 5. Myocardial apoptosis-related proteins in normal males, castrated males, and males treated with TRB after I/R. A: representative immunoblots. Active caspase-3 levels were increased in hearts from normal males compared with castrated males or males treated with TRB, whereas Bcl-2 expression was lower in normal males than in the other 2 groups. B: caspase-3 levels represented as % of procaspase-3 levels in untreated males, castrated males. and males treated with TRB. Results are means ± SE. *P < 0.05, **P < 0.01 vs. normal male. All samples were on the same membrane.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

View larger version (38K): [in this window] [in a new window]   Fig. 1. Changes in myocardial function after ischemia and reperfusion (I/R) in normal age-matched males (n = 12), castrated males (n = 8), and males treated with testosterone receptor blocker (TRB, flutamide; n = 9). A: left ventricular developed pressure (LVDP). B: left ventricular end-diastolic pressure (LVEDP). C: maximum positive first derivative of pressure (+dP/dt). D: –dP/dt. Results are means ± SE. *P < 0.01 vs. normal male at the corresponding time points.

Maximum +dP/dt and –dP/dt were impaired at the start of reperfusion. Normal male hearts demonstrated more depression of +dP/dt and increase of –dP/dt compared with castrated males and TRB-treated males (Fig. 1, C and D).

Myocardial p38 MAPK signaling pathway after I/R. The myocardial activation of phosphorylated p38 (active) and nonphosphorylated p38 (total) MAPK was assessed by Western blot. Total p38 MAPK was equivalent in normal males, castrated males, and males treated with TRB after I/R (Fig. 2). However, the phosphorylated forms of p38 MAPK were decreased in castrated males and males treated with TRB compared with normal males.

Myocardial inflammatory response to I/R. Myocardial production of TNF-, IL-1, and IL-6 was measured to investigate whether endogenous testosterone affects the myocardial inflammatory response to I/R injury (Fig. 3). Compared with normal males (TNF- 153.5 ± 6.78, IL-1 37.7 ± 13.5, and IL-6 1,449 ± 143.3 pg/mg protein), castrated males (TNF- 125.6 ± 8.70, IL-1 14.5 ± 2.89, and IL-6 1,105 ± 81.96 pg/mg protein) and males treated with TRB (TNF- 103.9 ± 6.84, IL-1 9.51 ± 2.03, and IL-6 998.6 ± 124 pg/mg protein) had less myocardial TNF-, IL-1, and IL-6 after I/R injury.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Effect of testosterone on myocardial TNF, IL-1, and IL-6 production after I/R. Cardiac TNF (A), IL-1 (B), and IL-6 (C) production were greater in rat hearts of normal males than of castrated males or males treated with TRB after I/R. Results are means ± SE; n = 4–6/group.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The main findings of the present study were that after I/R, compared with normal males, castrated males and males treated with testosterone receptor blockade (flutamide) 1) exhibited cardiac functional protection, 2) had decreased proinflammatory cytokine production (TNF-, IL-1, and IL-6) and active p38 MAPK and caspase-1, 3) had decreased expression of apoptosis-related proteins caspase-3 and caspase-11, and 4) had increased expression of antiapoptotic protein Bcl-2.

Sex differences exist in the response of myocardium to acute injury (3, 11, 32). Most studies have focused on the role of estrogen in cardiac protection, whereas few data exist regarding the effect of testosterone on cardiovascular disease. The role of testosterone in cardiac injury may be important because the heart can accumulate testosterone at higher concentrations than other androgen target organs (16), and functional androgen receptors are present in isolated cardiac myocytes (19). Furthermore, testosterone can modulate nuclear transcription by membrane receptor second messenger cascades (40); therefore, testosterone may be involved in mediating L-type calcium channel activity, coronary vasomotion by NO-dependent (4) and NO-independent mechanisms (42), and apoptotic cell death of cardiomyocytes (41, 43). In this study, rat hearts from castrated males and flutamide-treated males exhibited better functional recovery after acute I/R compared with normal males. This observation is consistent with other reports of protected cardiac performance in animals with testosterone depletion or testosterone receptor blockade after trauma-hemorrhage (29, 30) and suggests that endogenous testosterone may have a negative effect on the heart subjected to acute I/R.

Accumulating evidence indicates that cytokines are important mediators of injury-induced cardiovascular dysfunction. Acute injury in the form of ischemia, endotoxemia, or burn trauma results in myocardial functional suppression, in part via the local production of inflammatory mediators such as TNF- and IL-1. I/R injury induces the local production of TNF-, IL-1, and IL-6 (10, 20, 21, 33). Indeed, locally produced proinflammatory mediators may be important contributors to postischemic myocardial dysfunction and cardiomyocyte apoptosis. p38 MAPK has been shown to be an important mediator of TNF production. In our study, castrated males and TRB-treated males, both of which had improved postischemic functional recovery compared with normal males, also had less myocardial TNF-, IL-1, and Il-6 production and decreased p38 MAPK activation.

It remains unclear how I/R induces myocardial inflammatory cytokine production. One possible mechanism may involve myocardial p38 MAPK signaling. Stimuli such as I/R, oxidant stress, and hydrogen peroxide directly activate p38 MAPK (20). Activation of p38 MAPK is required for TNF- and IL-1 production in cardiomyocytes (24, 31, 37). TNF- production after I/R is dependent on NF-B translocation, which may occur via p38 MAPK activation, and regulation of this process occurs pretranscriptionally (20). On the other hand, caspase-1 and caspase-11 are shown to function upstream of IL-1 maturation (36). Caspase-1 is recognized as the IL-1-converting enzyme (ICE) for cleavage of IL-1 precursor to the mature form (7, 8). Precursor caspase-1 results in the generation of mature p10/p20, and p10/p20 form ICE (28). ICE is required for IL-1 activation in the postischemic heart (25). Furthermore, the activation of caspase-1 is dependent on caspase-11 (38). Caspase-11 is thought to activate downstream signals caspase-1 and caspase-3, and thus it may be important in both inflammation and apoptosis (13). It has been demonstrated that p38 MAPK mediates caspase-11 induction in microglia subjected to hypoxia and endotoxin exposure (12, 14). In the current study, we observed increased procaspase-1, but decreased caspase-1 p20 and caspase-11, in castrated males and TRB-treated males compared with untreated males.

Myocardial apoptosis is responsible for the loss of cardiomyocytes and depression of myocardial function after I/R. Myocyte apoptosis in heart failure is reduced in women compared with men (9). Apoptosis may be mediated by either the extrinsic death receptor signaling pathway or the intrinsic mitochondrial control pathway (15). Caspases play a crucial role in each of these pathways. The activation of the intrinsic apoptotic pathway (the release of cytochrome c and the activation of caspase-9) during reperfusion, but not ischemia, has been observed in chick cardiomyocytes (35), and activation of caspase-8 and caspase-3 occurs in response to hypoxia or ischemia (22). However, no information exists regarding the influence of testosterone on myocardial proapoptotic signaling cascades after acute I/R. In this study, we observed decreased activation of proapoptotic signaling cascade (caspase-3, caspase-11) and increased antiapoptotic Bcl-2 in castrated males and TRB-treated males compared with untreated male hearts after I/R. Clinically, anabolic androgenic steroid abuse has been associated with myocardial ischemia and sudden cardiac death (5). Some studies have demonstrated that anabolic androgenic steroids induce injury and apoptosis in myocardial cells (41, 43) and skeletal muscle cells in culture (1). Our observations of decreased apoptotic signaling with testosterone depletion or testosterone receptor blockade are consistent with these studies.

	ACKNOWLEDGMENTS

 
This work was supported in part by National Institute of General Medical Sciences R01-GM-070628 (D. R. Meldrum), the Clarian Values Fund (D. R. Meldrum), the Showalter Trust (D. R. Meldrum), and the Cryptic Masons Medical Research Foundation (D. R. Meldrum, M. Wang).

	FOOTNOTES

 

Address for reprint requests and other correspondence: D. R. Meldrum, 545 Barnhill Dr., Emerson Hall 215, Indianapolis, IN 46202 (E-mail: dmeldrum{at}iupui.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Abu-Shakra S, Alhalabi MS, Nachtman FC, Schemidt RA, and Brusilow WS. Anabolic steroids induce injury and apoptosis of differentiated skeletal muscle. J Neurosci Res 47: 186–197, 1997.[CrossRef][ISI][Medline]
2. Barp J, Araujo AS, Fernandes TR, Rigatto KV, Llesuy S, Bello-Klein A, and Singal P. Myocardial antioxidant and oxidative stress changes due to sex hormones. Braz J Med Biol Res 35: 1075–1081, 2002.[ISI][Medline]
3. Cavasin MA, Sankey SS, Yu AL, Menon S, and Yang XP. Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. Am J Physiol Heart Circ Physiol 284: H1560–H1569, 2003.[Abstract/Free Full Text]
4. Chou TM, Sudhir K, Hutchison SJ, Ko E, Amidon TM, Collins P, and Chatterjee K. Testosterone induces dilation of canine coronary conductance and resistance arteries in vivo. Circulation 94: 2614–2619, 1996.[Abstract/Free Full Text]
5. Dickerman RD, Schaller F, Prather I, and McConathy WJ. Sudden cardiac death in a 20-year-old bodybuilder using anabolic steroids. Cardiology 86: 172–173, 1995.[ISI][Medline]
6. Dougherty CJ, Kubasiak LA, Prentice H, Andreka P, Bishopric NH, and Webster KA. Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress. Biochem J 362: 561–571, 2002.[CrossRef][ISI][Medline]
7. Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M, Wong W, Kamen R, Tracey D, and Allen H. Caspase-1 processes IFN--inducing factor and regulates LPS-induced IFN- production. Nature 386: 619–623, 1997.[CrossRef][Medline]
8. Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, and Su MS. Activation of interferon- inducing factor mediated by interleukin-1 converting enzyme. Science 275: 206–209, 1997.[Abstract/Free Full Text]
9. Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, Kajstura J, and Anversa P. Myocyte death in the failing human heart is gender dependent. Circ Res 85: 856–866, 1999.[Abstract/Free Full Text]
10. Gwechenberger M, Mendoza LH, Youker KA, Frangogiannis NG, Smith CW, Michael LH, and Entman ML. Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions. Circulation 99: 546–551, 1999.[Abstract/Free Full Text]
11. Horton JW, White DJ, and Maass DL. Gender-related differences in myocardial inflammatory and contractile responses to major burn trauma. Am J Physiol Heart Circ Physiol 286: H202–H213, 2004.[Abstract/Free Full Text]
12. Hur J, Kim SY, Kim H, Cha S, Lee MS, and Suk K. Induction of caspase-11 by inflammatory stimuli in rat astrocytes: lipopolysaccharide induction through p38 mitogen-activated protein kinase pathway. FEBS Lett 507: 157–162, 2001.[CrossRef][ISI][Medline]
13. Kang SJ, Wang S, Hara H, Peterson EP, Namura S, Amin-Hanjani S, Huang Z, Srinivasan A, Tomaselli KJ, Thornberry NA, Moskowitz MA, and Yuan J. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol 149: 613–622, 2000.[Abstract/Free Full Text]
14. Kim NG, Lee H, Son E, Kwon OY, Park JY, Park JH, Cho GJ, Choi WS, and Suk K. Hypoxic induction of caspase-11/caspase-1/interleukin-1 in brain microglia. Brain Res Mol Brain Res 114: 107–114, 2003.[Medline]
15. Konopleva M, Zhao S, Xie Z, Segall H, Younes A, Claxton DF, Estrov Z, Kornblau SM, and Andreeff M. Apoptosis. Molecules and mechanisms. Adv Exp Med Biol 457: 217–236, 1999.[ISI][Medline]
16. Krieg M, Smith K, and Bartsch W. Demonstration of a specific androgen receptor in rat heart muscle: relationship between binding, metabolism, and tissue levels of androgens. Endocrinology 103: 1686–1694, 1978.[ISI][Medline]
17. Li D, Williams V, Liu L, Chen H, Sawamura T, Antakli T, and Mehta JL. LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation. Am J Physiol Heart Circ Physiol 283: H1795–H1801, 2002.[Abstract/Free Full Text]
18. Liao P, Wang SQ, Wang S, Zheng M, Zhang SJ, Cheng H, Wang Y, and Xiao RP. p38 Mitogen-activated protein kinase mediates a negative inotropic effect in cardiac myocytes. Circ Res 90: 190–196, 2002.[Abstract/Free Full Text]
19. Marsh JD, Lehmann MH, Ritchie RH, Gwathmey JK, Green GE, and Schiebinger RJ. Androgen receptors mediate hypertrophy in cardiac myocytes. Circulation 98: 256–261, 1998.[Abstract/Free Full Text]
20. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol Regul Integr Comp Physiol 274: R577–R595, 1998.[Abstract/Free Full Text]
21. Meldrum DR, Dinarello CA, Shames BD, Cleveland JC Jr, Cain BS, Banerjee A, Meng X, and Harken AH. Ischemic preconditioning decreases postischemic myocardial tumor necrosis factor- production. Potential ultimate effector mechanism of preconditioning. Circulation 98: II214–II218, 1998.
22. O'Mahoney ME, Logue S, Szegezdi E, Stenson-Cox C, Fitzgerald U, and Samali A. Hypoxia and ischemia induce nuclear condensation and caspase activation in cardiomyocytes. Ann NY Acad Sci 1010: 728–732, 2003.[Free Full Text]
23. Pantos C, Malliopoulou V, Paizis I, Moraitis P, Mourouzis I, Tzeis S, Karamanoli E, Cokkinos DD, Carageorgiou H, Varonos D, and Cokkinos DV. Thyroid hormone and cardioprotection: study of p38 MAPK and JNKs during ischaemia and at reperfusion in isolated rat heart. Mol Cell Biochem 242: 173–180, 2003.[CrossRef][ISI][Medline]
24. Peng T, Lu X, Lei M, Moe GW, and Feng Q. Inhibition of p38 MAPK decreases myocardial TNF- expression and improves myocardial function and survival in endotoxemia. Cardiovasc Res 59: 893–900, 2003.[Abstract/Free Full Text]
25. Pomerantz BJ, Reznikov LL, Harken AH, and Dinarello CA. Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1. Proc Natl Acad Sci USA 98: 2871–2876, 2001.[Abstract/Free Full Text]
26. Pugh PJ, Channer KS, Parry H, Downes T, and Jone TH. Bio-available testosterone levels fall acutely following myocardial infarction in men: association with fibrinolytic factors. Endocr Res 28: 161–173, 2002.[CrossRef][ISI][Medline]
27. Pugh PJ, Jones RD, Jones TH, and Channer KS. Intrinsic responses of rat coronary arteries in vitro: influence of testosterone, calcium, and effective transmural pressure. Endocrine 19: 155–161, 2002.[CrossRef][ISI][Medline]
28. Ramage P, Cheneval D, Chvei M, Graff P, Hemmig R, Heng R, Kocher HP, Mackenzie A, Memmert K, Revesz L, and Wishart W. Expression, refolding, and autocatalytic proteolytic processing of the interleukin-1-converting enzyme precursor. J Biol Chem 270: 9378–9383, 1995.[Abstract/Free Full Text]
29. Remmers DE, Cioffi WG, Bland KI, Wang P, Angele MK, and Chaudry IH. Testosterone: the crucial hormone responsible for depressing myocardial function in males after trauma-hemorrhage. Ann Surg 227: 790–799, 1998.[CrossRef][ISI][Medline]
30. Remmers DE, Wang P, Cioffi WG, Bland KI, and Chaudry IH. Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males. Am J Physiol Heart Circ Physiol 273: H2919–H2925, 1997.[Abstract/Free Full Text]
31. Salituro FG, Germann UA, Wilson KP, Bemis GW, Fox T, and Su MS. Inhibitors of p38 MAP kinase: therapeutic intervention in cytokine-mediated diseases. Curr Med Chem 6: 807–823, 1999.[ISI][Medline]
32. Song X, Li G, Vaage J, and Valen G. Effects of sex, gonadectomy, and oestrogen substitution on ischaemic preconditioning and ischaemia-reperfusion injury in mice. Acta Physiol Scand 177: 459–466, 2003.[CrossRef][ISI][Medline]
33. Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y, and Yacoub MH. Overexpression of interleukin-1 receptor antagonist provides cardioprotection against ischemia-reperfusion injury associated with reduction in apoptosis. Circulation 104: I308–I313, 2001.
34. Tunstall-Pedoe H, Morrison C, Woodward M, Fitzpatrick B, and Watt G. Sex differences in myocardial infarction and coronary deaths in the Scottish MONICA population of Glasgow 1985 to 1991. Presentation, diagnosis, treatment, and 28-day case fatality of 3991 events in men and 1551 events in women. Circulation 93: 1981–1992, 1996.[Abstract/Free Full Text]
35. Vanden Hoek TL, Qin Y, Wojcik K, Li CQ, Shao ZH, Anderson T, Becker LB, and Hamann KJ. Reperfusion, not simulated ischemia, initiates intrinsic apoptosis injury in chick cardiomyocytes. Am J Physiol Heart Circ Physiol 284: H141–H150, 2003.[Abstract/Free Full Text]
36. Wang J and Lenardo MJ. Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies. J Cell Sci 113: 753–757, 2000.[Abstract]
37. Wang M, Sankula R, Tsai BM, Meldrum KK, Turrentine M, March KL, Brown JW, Dinarello CA, and Meldrum DR. p38 MAPK mediates myocardial proinflammatory cytokine production and endotoxin-induced contractile suppression. Shock 21: 170–174, 2004.[CrossRef][ISI][Medline]
38. Wang S, Miura M, Jung YK, Zhu H, Li E, and Yuan J. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92: 501–509, 1998.[CrossRef][ISI][Medline]
39. Webb CM, Adamson DL, de Zeigler D, and Collins P. Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 83: 437–439, 1999.[CrossRef][ISI][Medline]
40. Wehling M. Specific, nongenomic actions of steroid hormones. Annu Rev Physiol 59: 365–393, 1997.[CrossRef][ISI][Medline]
41. Welder AA, Robertson JW, Fugate RD, and Melchert RB. Anabolic-androgenic steroid-induced toxicity in primary neonatal rat myocardial cell cultures. Toxicol Appl Pharmacol 133: 328–342, 1995.[CrossRef][ISI][Medline]
42. Yue P, Chatterjee K, Beale C, Poole-Wilson PA, and Collins P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 91: 1154–1160, 1995.[Abstract/Free Full Text]
43. Zaugg M, Jamali NZ, Lucchinetti E, Xu W, Alam M, Shafiq SA, and Siddiqui MA. Anabolic-androgenic steroids induce apoptotic cell death in adult rat ventricular myocytes. J Cell Physiol 187: 90–95, 2001.[CrossRef][ISI][Medline]

This article has been cited by other articles:

				M. P. Hutchens, J. Dunlap, P. D. Hurn, and P. O. Jarnberg Renal Ischemia: Does Sex Matter? Anesth. Analg., July 1, 2008; 107(1): 239 - 249. [Abstract] [Full Text] [PDF]

				R. Ray, C. M. Herring, T. A. Markel, P. R. Crisostomo, M. Wang, B. Weil, T. Lahm, and D. R. Meldrum Deleterious effects of endogenous and exogenous testosterone on mesenchymal stem cell VEGF production Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1498 - R1503. [Abstract] [Full Text] [PDF]

				P. D. Metcalfe, J. A. Leslie, M. T. Campbell, D. R. Meldrum, K. L. Hile, and K. K. Meldrum Testosterone exacerbates obstructive renal injury by stimulating TNF-{alpha} production and increasing proapoptotic and profibrotic signaling Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E435 - E443. [Abstract] [Full Text] [PDF]

				D. S. Hydock, C.-Y. Lien, C. M. Schneider, and R. Hayward Effects of voluntary wheel running on cardiac function and myosin heavy chain in chemically gonadectomized rats Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3254 - H3264. [Abstract] [Full Text] [PDF]

				T. Lahm, K. M. Patel, P. R. Crisostomo, T. A. Markel, M. Wang, C. Herring, and D. R. Meldrum Endogenous estrogen attenuates pulmonary artery vasoreactivity and acute hypoxic pulmonary vasoconstriction: the effects of sex and menstrual cycle Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E865 - E871. [Abstract] [Full Text] [PDF]

				M. Wang, T. Markel, P. Crisostomo, C. Herring, K. K. Meldrum, K. D. Lillemoe, and D. R. Meldrum Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1694 - H1699. [Abstract] [Full Text] [PDF]

				R. E. Petre, M. P. Quaile, E. I. Rossman, S. J. Ratcliffe, B. A. Bailey, S. R. Houser, and K. B. Margulies Sex-based differences in myocardial contractile reserve Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R810 - R818. [Abstract] [Full Text] [PDF]

				P. R. Crisostomo, M. Wang, G. M. Wairiuko, E. D. Morrell, and D. R. Meldrum Brief exposure to exogenous testosterone increases death signaling and adversely affects myocardial function after ischemia Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1168 - R1174. [Abstract] [Full Text] [PDF]

				M. A. Cavasin, Z.-Y. Tao, A.-L. Yu, and X.-P. Yang Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2043 - H2050. [Abstract] [Full Text] [PDF]

				D. R. Meldrum Estrogen increases protective proteins following trauma and hemorrhage Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R809 - R811. [Full Text] [PDF]

				J. M. Pitcher, M. Wang, B. M. Tsai, A. Kher, N. T. Nelson, and D. R. Meldrum Endogenous estrogen mediates a higher threshold for endotoxin-induced myocardial protection in females Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R27 - R33. [Abstract] [Full Text] [PDF]

				M. Wang, B. M. Tsai, M. W. Turrentine, Y. Mahomed, J. W. Brown, and D. R. Meldrum p38 Mitogen Activated Protein Kinase Mediates Both Death Signaling and Functional Depression in the Heart Ann. Thorac. Surg., December 1, 2005; 80(6): 2235 - 2241. [Abstract] [Full Text] [PDF]

				R. Sheppard, M. Bedi, T. Kubota, M. J. Semigran, W. Dec, R. Holubkov, A. M. Feldman, W. D. Rosenblum, C. F. McTiernan, D. M. McNamara, et al. Myocardial Expression of Fas and Recovery of Left Ventricular Function in Patients With Recent-Onset Cardiomyopathy J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1036 - 1042. [Abstract] [Full Text] [PDF]

				A. Kher, K. K. Meldrum, M. Wang, B. M. Tsai, J. M. Pitcher, and D. R. Meldrum Cellular and molecular mechanisms of sex differences in renal ischemia-reperfusion injury Cardiovasc Res, September 1, 2005; 67(4): 594 - 603. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 288/1/H221    most recent 00784.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (32) Citing Articles via Google Scholar Google Scholar Articles by Wang, M. Articles by Meldrum, D. R. Search for Related Content PubMed PubMed Citation Articles by Wang, M. Articles by Meldrum, D. R.