Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats

Tavernier, B.; Li, Jianmei; El–Omar, Magdi; Lanone, Sophie; Yang, Zhaokang; Trayer, Ian P.; Mebazaa, Alexandre; Shah, Ajay

doi:10.1096/fj.00-0433fje

Cited by 91 publications

(99 citation statements)

References 32 publications

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“…9,[11][12][13] Along with cardiomyocyte caspase-3 activation, endotoxin treatment induced major reduction of contractile function with troponin T cleavage and sarcomere disarray. Endotoxin also produced alterations in myofilament Ca 2ϩ response, 16,19 which may participate in the septic myocardial dysfunction. Importantly, functional and morphological alterations of septic cardiomyocytes were prevented by caspase inhibitor zVAD.fmk, suggesting that caspase-3 activation may underlie, at least part, cardiomyocyte contractile dysfunction and calcium homeostasis perturbations.…”

Section: Discussionmentioning

confidence: 99%

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

et al. 2005

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Background-Although most of the deleterious effects of sepsis-induced apoptosis have been attributed to increased lymphocyte cell death, caspase activation may directly alter cell function of different organ systems. We postulated that left ventricular (LV) cardiomyocyte caspase activation is directly involved in sepsis-induced heart contractile dysfunction. Methods and Results-LV cardiomyocytes isolated 4 hours after rat treatment with endotoxin injection (10 mg/kg) displayed major reductions in contractile reserve and myofilament response to Ca 2ϩ . Concomitantly, endotoxin also induced increases in LV cardiomyocyte caspase-3, -8, and -9-like activities, which were associated with sarcomeric structure destruction and cleavage of components of the cardiac myofilament. Interestingly, zVAD.fmk treatment of septic rat prevented LV cardiomyocyte contractile dysfunction, reductions in myofilament response to calcium, troponin T cleavage, and sarcomere destruction. Serum (10%) of endotoxin-treated rats induced contractile dysfunction, caspase-3-like activity increase, and troponin T cleavage of naive LV cardiomyocytes. The effects of septic serum were prevented in LV cardiomyocytes isolated from zVAD.fmk-or zDEVD.cmk-treated rats or LV cardiomyocytes preincubated with zVAD.fmk or zDEVD.cmk. Conclusions-The

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Section: Discussionmentioning

confidence: 99%

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

et al. 2005

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“…Whether these findings might have an impact on organ function or integrity remains unknown. However, it is of interest that cardiac dysfunction (suppressed Ca 2ϩ sensitivity with decreased contractility [12,13]) and lung injury (acute respiratory distress syndrome) are commonplace in sepsis syndrome. This raises the intriguing but highly speculative question of whether tissue Fe loading potentially could worsen clinical sepsis syndrome or outcomes.…”

Section: Sites Of Fe-mediated Tnf-␣ Productionmentioning

confidence: 99%

Parenteral Iron Compounds

Zager

2006

Clinical Journal of the American Society of Nephrology

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Ferric iron (Fe)-carbohydrate complexes are widely used for treating Fe deficiency in patients who are unable to meet their Fe requirements with oral supplements. Intravenous Fe generally is well tolerated and effective in correcting Fe-deficient states. However, the complexing of Fe to carbohydrate polymers does not block its potent pro-oxidant effects; systemic free radical generation and, possibly, tissue damage may result. The purpose of this review is to (1) underscore the capacity of currently used parenteral Fe formulations to induce oxidative stress, (2) compare the severity of these oxidant reactions with those that result from unshielded Fe salts and with each other, and (3) speculate as to the potential of these agents to induce acute renal cell injury and augment systemic inflammatory responses. The experimental data that are reviewed should not be extrapolated to the clinical setting or be used for clinical decision making. Rather, it is hoped that the information provided herein may have utility for clinical hypothesis generation and, hence, future clinical studies. By so doing, a better understanding of Fe's potential protean effects on patients with renal disease may result.

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“…Moreover, two independent groups have reported that transgenic replacement of native cTnI with the ␤-adrenergic phospho-mimetic cTnI (to mimic constitutive phosphorylation) resulted in the reduction of cardiomyocyte calcium sensitivity (32,33). In addition, it has been reported that increased PKA-dependent phosphorylation of cTnI leads to a reduction in myofilament calcium sensitivity and blunted ␤-adrenergic response (34). Therefore, the increased phosphorylation of cTnI in PMCA4b-TG hearts may desensitize the myofibril to calcium and may compensate for the effect of the .…”

Section: Discussionmentioning

confidence: 99%

Specific Role of Neuronal Nitric-oxide Synthase when Tethered to the Plasma Membrane Calcium Pump in Regulating the β-Adrenergic Signal in the Myocardium

Mohamed

Oceandy

Prehar

et al. 2009

Journal of Biological Chemistry

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The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a modulator of cardiac contractility. We have demonstrated previously that isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart and that this complex regulates ␤-adrenergic signal transmission in vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG) showed a significant reduction in nNOS and total NOS activities as well as in cGMP levels in the heart compared with their wild type (WT) littermates. In contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a 3-fold increase in Ser 16 phospholamban (PLB) phosphorylation as well as Ser 22 and Ser 23 cardiac troponin I (cTnI) phosphorylation at base line compared with the WT. In addition, the relative induction of PLB phosphorylation and cTnI phosphorylation following isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining the blunted physiological response to the ␤-adrenergic stimulation. In keeping with the data from the transgenic animals, neonatal rat cardiomyocytes overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP levels. This was accompanied by an increase in cAMP levels, which led to an increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP levels were likely due to the modulation of cardiac phosphodiesterase, which determined the balance between cGMP and cAMP following PMCA4b overexpression. In conclusion, these results showed that the nNOSPMCA4b complex regulates contractility via cAMP and phosphorylation of both PLB and cTnI.

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Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats

Cited by 91 publications

References 32 publications

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

Parenteral Iron Compounds

Specific Role of Neuronal Nitric-oxide Synthase when Tethered to the Plasma Membrane Calcium Pump in Regulating the β-Adrenergic Signal in the Myocardium

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