Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following cardiopulmonary bypass (CPB) and cardiac global ischemia and reperfusion, proinflammatory genes are up-regulated, and nuclear factor (NF)-kappaB is involved in this regulation. We studied whether inactivation of NF-kappaB could decrease myocardial ischemia/reperfusion injury with cardioplegia during CPB, attenuate matrix metalloproteinase (MMP) activation, and prevent cardiac mechanical dysfunction. Rabbits received normal saline (group 1) or curcumin (70 and 7 micromol/kg in groups 2 and 3) injection 2 hours before CPB. Total CPB was initiated, and myocardial protection was delivered every 20 minutes for 60 minutes of cardiac arrest. Rabbits were weaned from CPB and reperfused for 4 hours before the hearts were harvested. Blood was sampled at various time points. Postoperative expression of myocardial mRNA levels of interleukin 6, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha, postreperfusion plasma level of troponin I, and cardiac mechanical dysfunction were significantly decreased in the curcumin groups. The myocardial levels of activated MMP-2 and -9 were also significantly reduced compared with the control group. In conclusion, by inhibiting NF-kappaB activation, the up-regulation of cardiac proinflammatory genes can be ameliorated, and the activation of MMPs can be decreased during CPB, thereby lessening severity of cardiac mechanical dysfunction after global cardiac ischemia/reperfusion injury.
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PMID:Inhibition of NF-kappa B activation can attenuate ischemia/reperfusion-induced contractility impairment via decreasing cardiomyocytic proinflammatory gene up-regulation and matrix metalloproteinase expression. 1577 17

Decreased Ca2+ responsiveness of the myofilaments underlies myocardial stunning. Given that cross-bridge cycling is a major determinant of myofilament behavior, we quantified cross-bridge cycling rate in stunned myocardium. After stabilization, rat hearts were subjected to 20 min of no-flow global ischemia and 30 min of reperfusion at 37 degrees C. Control hearts were perfused continuously at 37 degrees C for 60 min. Trabeculae were dissected and chemically skinned with 1% Triton X-100. The muscles were then activated with solutions of varied Ca2+ concentration ([Ca2+]). Force-[Ca2+] relations, rate of force redevelopment after release (k(tr)), muscle stiffness (k(m)), and myofilament ATP consumption were determined. Maximal Ca2+-activated force (Fmax) was depressed in stunned myocardium (49 +/- 5 vs. 82 +/- 5 mN/mm2, P < 0.01). Western immunoblotting showed degradation of troponin I in stunned myocardium. The k(tr) at Fmax was significantly increased in stunned muscles (19.82 +/- 2.74 vs. 13.19 +/- 0.96 s(-1), 22 degrees C, P < 0.01; 7.49 +/- 0.52 vs. 5.81 +/- 0.54 s(-1), 10 degrees C, P < 0.05). The ratio of k(m) measured at 100 Hz over that at 1 Hz, during Fmax, is lower in stunned muscles (8.22 +/- 1.56 vs. 12.94 +/- 0.71, P < 0.05). In comparison with k(m) at rigor, k(m) at Fmax is significantly lower in the stunned group (78.82 +/- 6.11 vs. 93.27 +/- 3.03%, P < 0.05). Myofilament ATP consumption at Fmax did not change in stunned muscles (5,901 +/- 952 vs. 5,596 +/- 972 pmol x microl(-1) x min(-1), P = 0.49). These results show that cross-bridge cycling is increased in stunned myocardium. Such increases are likely the result of increased transition rate from force-generating states to non-force-generating states. Thus stunned myocardium still maintains ATP consumption in spite of lower force development, rationalizing the long-standing paradox of decreased force but unchanged oxygen consumption in the postischemic heart.
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PMID:Increased cross-bridge cycling rate in stunned myocardium. 1617 65

Calpain-1 is a ubiquitous intracellular Ca2+-activated protease, which has been implicated in the pathogenesis of reversible myocardial depression (i.e. myocardial stunning) that follows ischemia and reperfusion via myofibrillar protein degradation. However, the target proteins of this degradative process in the human myocardium have not yet been identified. In order to compare the levels of Calpain-1 susceptibility within a set of human myofibrillar proteins (titin, alpha-fodrin, desmin, troponin T (cTnT), troponin I (cTnI) and alpha-actinin), crude left ventricular tissue homogenates were incubated for 0.5, 15, 30, 60 or 120 min in the presence of Calpain-1 (1 U or 5 U). Differences in the kinetics and extents of protein degradation were subsequently evaluated by using silver-stained SDS-polyacrylamide gels and Western immunoblot analyses. These assays revealed myofibrillar proteins with high (titin and alpha-fodrin), moderate (desmin and cTnT), or low (cTnI and alpha-actinin) relative Calpain-1 susceptibilities. The level of phosphorylation of cTnI did not explain its relatively low Calpain-1 susceptibility. Moreover, the molecular mass distributions of the truncated alpha-fodrin, desmin and cTnI fragments resulting from Ca2+-dependent autoproteolysis exhibited marked similarities with those of their Calpain-1-clipped products. These in vitro results shed light on a number of structural (titin, alpha-fodrin, desmin and alpha-actinin) and regulatory (cTnT and cTnI) proteins within the contractile apparatus as potential targets of Calpain-1. Their degradation may contribute to the development of postischemic stunning in the human myocardium.
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PMID:Calpain-1-sensitive myofibrillar proteins of the human myocardium. 1618 82

Although great achievements have been made in elucidating the molecular mechanisms contributing to acute myocardial ischemia/reperfusion (I/R) injury, an effective pharmacological therapy to protect cardiac tissues from serious damage associated with acute myocardial infarction, coronary arterial bypass grafting surgery, or acute coronary syndromes has not been developed. We examined the in vivo cardioprotective effects of caffeic acid phenethyl ester (CAPE), a natural product with potent anti-inflammatory, antitumor, and antioxidant activities. CAPE was systemically delivered to rabbits either 60 min before or 30 min after surgically inducing I/R injury. Infarct dimensions in the area at risk were reduced by >2-fold (P < 0.01) with CAPE treatment at either period. Accordingly, serum levels of normally cytosolic enzymes lactate dehydrogenase, creatine kinase (CK), MB isoenzyme of CK, and cardiac-specific troponin I were markedly reduced in both CAPE treatment groups (P < 0.05) compared with the vehicle-treated control group. CAPE-treated tissues displayed significantly less cell death (P < 0.05), which was in part due to inhibition of p38 mitogen-activated protein kinase activation and reduced DNA fragmentation often associated with caspase 3 activation (P < 0.05). In addition, CAPE directly blocked calcium-induced cytochrome c release from mitochondria. Finally, the levels of inflammatory proteins IL-1beta and TNF-alpha expressed in the area at risk were significantly reduced with CAPE treatment (P < 0.05). These data demonstrate that CAPE has potent cardioprotective effects against I/R injury, which are mediated, at least in part, by the inhibition of inflammatory and cell death responses. Importantly, protection is conferred when CAPE is systemically administered after the onset of ischemia, thus demonstrating potential efficacy in the clinical scenario.
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PMID:Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury. 1621 15

The severity and duration of ischemia-reperfusion injury is hypothesized to play an important role in the ability of the heart subsequently to recover contractility. Permeabilized trabeculae were prepared from a rat model of ischemia-reperfusion injury to examine the impact on force generation. Compared with the control perfused condition, the maximum force (F(max)) per cross-sectional area and the rate of tension redevelopment of Ca(2+)-activated trabeculae fell by 71% and 44%, respectively, during ischemia despite the availability of a high concentration of ATP. The reduction in F(max) with ischemia was accompanied by a decline in fiber stiffness, implying a drop in the absolute number of attached cross bridges. However, the declines during ischemia were largely recovered after reperfusion, leading to the hypothesis that intrinsic, reversible posttranslational modifications to proteins of the contractile filaments occur during ischemia-reperfusion injury. Examination of thin-filament proteins from ischemic or ischemia-reperfused hearts did not reveal proteolysis of troponin I or T. However, actin was found to be glutathionylated with ischemia. Light-scattering experiments demonstrated that glutathionylated G-actin did not polymerize as efficiently as native G-actin. Although tropomyosin accelerated the time course of native and glutathionylated G-actin polymerization, the polymerization of glutathionylated G-actin still lagged native G-actin at all concentrations of tropomyosin tested. Furthermore, cosedimentation experiments demonstrated that tropomyosin bound glutathionylated F-actin with significantly reduced cooperativity. Therefore, glutathionylated actin may be a novel contributor to the diverse set of posttranslational modifications that define the function of the contractile filaments during ischemia-reperfusion injury.
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PMID:Decline of contractility during ischemia-reperfusion injury: actin glutathionylation and its effect on allosteric interaction with tropomyosin. 1625 71

The myofilament protein troponin I (TnI) has a key isoform-dependent role in the development of contractile failure during acidosis and ischemia. Here we show that cardiac performance in vitro and in vivo is enhanced when a single histidine residue present in the fetal cardiac TnI isoform is substituted into the adult cardiac TnI isoform at codon 164. The most marked effects are observed under the acute challenges of acidosis, hypoxia, ischemia and ischemia-reperfusion, in chronic heart failure in transgenic mice and in myocytes from failing human hearts. In the isolated heart, histidine-modified TnI improves systolic and diastolic function and mitigates reperfusion-associated ventricular arrhythmias. Cardiac performance is markedly enhanced in transgenic hearts during reperfusion despite a high-energy phosphate content similar to that in nontransgenic hearts, providing evidence for greater energetic economy. This pH-sensitive 'histidine button' engineered in TnI produces a titratable molecular switch that 'senses' changes in the intracellular milieu of the cardiac myocyte and responds by preferentially augmenting acute and long-term function under pathophysiological conditions. Myofilament-based inotropy may represent a therapeutic avenue to improve myocardial performance in the ischemic and failing heart.
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PMID:Histidine button engineered into cardiac troponin I protects the ischemic and failing heart. 1642 45

The peroxynitrite-mediated activation of matrix metalloproteinase-2 (MMP-2) and subsequent cleavage of troponin I (TnI) in ventricular myocytes is a detrimental effect of ischemia/reperfusion injury. We hypothesized that acetaminophen, an effective antioxidant against peroxynitrite, would attenuate activation of MMP-2 and improve cardiac mechanical function. Isolated, perfused guinea pig hearts (Langendorff) were treated with either acetaminophen [0.35 mmol/l] or its vehicle and administered a bolus injection of peroxynitrite (6 microM) after reaching steady state function. Hemodynamic, metabolic, and mechanical effects were recorded, and coronary effluent concentrates or supernatant from heart homogenates were subjected to Western blotting and gelatin zymography. Hemodynamic and metabolic data showed no difference between acetaminophen- and vehicle-treated hearts. Mechanical data revealed that treatment with acetaminophen preserved contractile function (particularly diastolic function) after peroxynitrite administration. For example, 5 min after administration of peroxynitrite percent baseline -dP/dt(max) was 10+/-3% and -4+/-7% (P<0.05) in acetaminophen- and vehicle-treated hearts, respectively. Western blotting and gel zymography revealed higher 72 kDa (pro-MMP-2) proteolytic activity in heart homogenates of vehicle-treated versus acetaminophen-treated hearts. In addition, Western blotting of heart homogenates showed increased degradative products of TnI in vehicle-treated versus acetaminophen-treated hearts. We conclude that acetaminophen is cardioprotective, at least in part, by attenuating peroxynitrite-activated, MMP-2-mediated cleavage of TnI.
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PMID:Acetaminophen attenuates peroxynitrite-activated matrix metalloproteinase-2-mediated troponin I cleavage in the isolated guinea pig myocardium. 1653 Jul 85

This study has been conducted in an effort to establish metabolic and inflammatory responses of the myocardium during aortic valve surgery on the beating heart with CPB and continuous coronary sinus perfusion with normothermic blood. Twenty patients, divided into two groups, participated in this study. Conventional aortic valvular operations were performed on first 10 patients, while the second group, consisting of 10 patients as well, was subjected to the operations with CPB on the beating heart with continuously perfusion with blood through coronary sinus. There were total of 14 biological and 6 mechanical valves implanted in aortic position. In this study, cardiac markers and inflammatory mediators IL-8 and TNF, were measured preoperatively and postoperatively. Metabolic changes were documented based on the levels of CK-MB, troponin I, myoglobin and LDH. Inflammatory factors we measured through IL-8 and TNF. All measurements were taken in 6 hour intervals during the initial 48 hours following the operations. The patients of "the beating heart" group had significantly lower dose of markers and cytokines in comparison to those who had undergone the conventional valvular operation. The elimination of the adverse effects of global ischemia produced from reperfusion injury and the similarity to the physiological condition, suggests that the revival of the beating heart procedure is more reasonable. This procedure of valvular surgery on the beating heart can be one of the good surgical options for the high-risk valvular patients.
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PMID:Inflammatory and metabolic response of the myocardium during aortic valve surgery on the beating heart. 1687 16

The cardiac myofilaments consist of a highly ordered assembly of proteins that collectively generate force in a calcium-dependent manner. Defects in myofilament function and its regulation have been implicated in various forms of acquired and inherited human heart disease. For example, during cardiac ischemia, cardiac myocyte contractile performance is dramatically downregulated due in part to a reduced sensitivity of the myofilaments to calcium under acidic pH conditions. Over the last several years, the thin filament regulatory protein, troponin I, has been identified as an important mediator of this response. Mutations in troponin I and other sarcomere genes are also linked to several distinct inherited cardiomyopathic phenotypes, including hypertrophic, dilated, and restrictive cardiomyopathies. With the cardiac sarcomere emerging as a central player for such a diverse array of human heart diseases, genetic-based strategies that target the myofilament will likely have broad therapeutic potential. The development of safe vector systems for efficient gene delivery will be a critical hurdle to overcome before these types of therapies can be successfully applied. Nonetheless, studies focusing on the principles of acute genetic engineering of the sarcomere hold value as they lay the essential foundation on which to build potential gene-based therapies for heart disease.
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PMID:Genetic engineering and therapy for inherited and acquired cardiomyopathies. 1713

With the introduction of biomarkers like troponin I (cTnI), our ability to identify and quantify myocardial infarction in the postoperative period has been greatly enhanced. Even small elevations of cTnI should be considered as a myocardial infarction. Small increases in cTnI postoperatively have indeed been found to be associated with worse short and long-term outcomes, the higher the cTnI level the worse the outcome. Studies undertaken in the 1980s when postoperative myocardial infarction (PMI) was detected by means of electrocardiogram recordings every 12 hours following operation suggested that this complication occurred on the second or third postoperative day. More recent studies where postoperative myocardial necrosis has been detected by repeated troponin dosages have revealed that, in fact, postoperative myocardial infarction appears much earlier between 12 and 32 hour after the end of surgery. Two types of PMI were identified based on intense troponin surveillance. They stem from two different major pathophysiological mechanisms. One seems to be related to plaque-vulnerability, while the other may be due to the effects of prolonged ischemia. The postoperative period should be regarded as a vulnerable period' that acts synergistically with both plaque and patient vulnerabilities in the development of PMI. Monitoring troponin levels in the postoperative period following surgery enables the identification of patients with myocardial damage and the institution of early aggressive intervention (e.g., intensive beta blockers therapy, adequate analgesia, correction of anemia) in order to prevent the evolution of PMI during this golden period' that lasts about two days. In patients that are prone to develop PMI, and especially in those who are prone to develop PMI related to plaque rupture, prevention can be achieved by better preoperative identification of the vulnerable plaque, and by a better plaque stabilization, either metabolically (e.g., statins) or by actual coronary stenting. Further understanding of the mechanisms underlying PMI, as well as their early identification, may contribute to the reduction of the incidence of PMI and its associated morality in the future.
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PMID:Postoperative myocardial infarction: pathophysiology, new diagnostic criteria, prevention. 1723 64


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