Featured Article: The loss of copper is associated with the increase in copper metabolism MURR domain 1 in ischemic hearts of mice

The distribution of copper (Cu) in the biological system is regulated by Cu transporters and chaperones. It has been known for a long time that myocardial ischemia is accompanied by the loss of Cu from the heart, but the mechanism by which this occurs remains unknown. The present study was undertaken to understand the relationship between Cu loss and alterations in Cu transporters during the pathogenesis of myocardial ischemia. Male mice (C57 BL/6J) were subjected to left anterior descending (LAD) coronary artery ligation to induce myocardial ischemia. Changes in Cu concentrations in serum and hearts were determined from blood and tissue samples harvested at different time points for a total of 28 days after the operation. Cu concentrations in the ischemic myocardium were continuously decreased starting at the fourth day after LAD artery ligation, gradually depleted by more than 80% of the normal level at the 10th day, and remained at the lowest level (about 20% of normal levels) thereafter. Serum Cu concentrations were correspondingly increased starting at the fourth day, reached to the highest level between day 7 and 10, and gradually recovered to the normal level until 21st day after the operation. Along with the same time course, the intracellular Cu exporter copper metabolism MURR domain 1 (COMMD1) was significantly and sustainably increased, but ATP7A and ATP7B were not significantly changed in the ischemic myocardium. These results suggest that during the pathogenesis of myocardial ischemia, COMMD1 would play a critical role in exporting Cu from the ischemic myocardium to the blood. Impact statement In this work, we found that copper efflux from the ischemic heart leads to the elevation of serum copper concentrations, addressing a long-term question related to serum copper elevation in myocardial ischemia patients. The efflux of copper from the ischemic heart results at least in part from the upregulation of copper metabolism MURR domain 1 (COMMD1) in the heart upon ischemic insult. This work provides a novel insight into copper homeostasis and alteration in cardiovascular system.

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Lack of a significant protective effect of augmented circulating glucose on the ischemic myocardium

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y76-060 ◽

1976 ◽

Vol 54 (4) ◽

pp. 423-429 ◽

Cited By ~ 3

Author(s):

James A. Spath Jr. ◽

Martin L. Ogletree ◽

Allan M. Lefer

Keyword(s):

Myocardial Ischemia ◽

Protective Effect ◽

Creatine Phosphokinase ◽

Ischemic Myocardium ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

The Status ◽

Effect Of Glucose ◽

Significant Protective Effect

Infusion of glucose alone or glucose with insulin in cats subjected to acute myocardial ischemia did not alter the hemodynamic response of the cats to coronary artery ligation. Furthermore, determination of myocardial creatine phosphokinase (CPK) (ATP:creatine N-phosphotransferase, EC 2.7.3.2) activities failed to reveal a protective effect of glucose and insulin upon the status of the developing infarct in the ischemic myocardium. However, glucose and insulin apparently promote clearance of CPK from the plasma and inhibit proteolysis during the early phase of myocardial ischemia. These actions may be of value in generalized adaptive response of the animal to the stress of ischemia, but does not per se appear to diminish the spread of the ischemic damage within the heart nor to limit the extension of the evolving infarct.

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Central mineralocorticoid receptor blockade decreases plasma TNF-α after coronary artery ligation in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00376.2002 ◽

2003 ◽

Vol 284 (2) ◽

pp. R328-R335 ◽

Cited By ~ 40

Author(s):

Joseph Francis ◽

Robert M. Weiss ◽

Alan Kim Johnson ◽

Robert B. Felder

Keyword(s):

Heart Failure ◽

Central Nervous System ◽

Nervous System ◽

Mineralocorticoid Receptor ◽

Critical Role ◽

Evaluation Study ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Tnf Α ◽

The Central Nervous System

The Randomized Aldactone Evaluation Study (RALES) demonstrated a substantial clinical benefit to blocking the effects of aldosterone (Aldo) in patients with heart failure. We recently demonstrated that the enhanced renal conservation of sodium and water in rats with heart failure can be reduced by blocking the central nervous system effects of Aldo with the mineralocorticoid receptor (MR) antagonist spironolactone (SL). Preliminary data from our laboratory suggested that central MR might contribute to another peripheral mechanism in heart failure, the release of proinflammatory cytokines. In the present study, SL (100 ng/h for 21 days) or ethanol vehicle (Veh) was administered via the 3rd cerebral ventricle to one group of rats after coronary ligation (CL) or sham CL (Sham) to induce congestive heart failure (CHF). In Veh-treated CHF rats, tumor necrosis factor-α (TNF-α) levels increased during day 1 and continued to increase throughout the 3-wk observation period. In CHF rats treated with SL, started 24 h after CL, TNF-α levels rose initially but retuned to control levels by day 5 after CL and remained low throughout the study. These findings suggest that activation of MR in the central nervous system plays a critical role in regulating TNF-α release in heart failure rats. Thus some of the beneficial effect of blocking MR in heart failure could be due at least in part to a reduction in TNF-α production.

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A Simple Modification Results in Greater Success in the Model of Coronary Artery Ligation and Myocardial Ischemia in Mice

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0b013e318288a68d ◽

2013 ◽

Vol 61 (5) ◽

pp. 430-436 ◽

Cited By ~ 5

Author(s):

Xiao-Long Liao ◽

Xiao-Xia Hu ◽

Feng-Jun Chang ◽

Hai-Yun Yuan ◽

Hong-Bo Ci ◽

...

Keyword(s):

Coronary Artery ◽

Myocardial Ischemia ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Simple Modification

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Dang Gui Bu Xue Tang ameliorates coronary artery ligation-induced myocardial ischemia in rats

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.01.079 ◽

2017 ◽

Vol 88 ◽

pp. 617-624 ◽

Cited By ~ 5

Author(s):

Ma Chunhua ◽

Long Hongyan ◽

Zhu Weina ◽

He Xiaoli ◽

Zhang Yajie ◽

...

Keyword(s):

Coronary Artery ◽

Myocardial Ischemia ◽

Coronary Artery Ligation ◽

Artery Ligation

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Central mineralocorticoid receptor blockade improves volume regulation and reduces sympathetic drive in heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.5.h2241 ◽

2001 ◽

Vol 281 (5) ◽

pp. H2241-H2251 ◽

Cited By ~ 106

Author(s):

Joseph Francis ◽

Robert M. Weiss ◽

Shun-Guang Wei ◽

Alan Kim Johnson ◽

Terry G. Beltz ◽

...

Keyword(s):

Heart Failure ◽

Central Nervous System ◽

Nervous System ◽

Volume Regulation ◽

Critical Role ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Water Excretion ◽

Beneficial Effects ◽

The Central Nervous System

The mineralocorticoid (MC) receptor antagonist spironolactone (SL) improves morbidity and mortality in patients with congestive heart failure (CHF). We tested the hypothesis that the central nervous system actions of SL contribute to its beneficial effects. SL (100 ng/h for 28 days) or ethanol vehicle (VEH) was administered intracerebroventricularly or intraperitoneally to rats with CHF induced by coronary artery ligation (CL) and to SHAM-operated controls. The intracerebroventricular SL treatment prevented the increase in sodium appetite and the decreases in sodium and water excretion observed within a week of CL in VEH-treated CHF rats. Intraperitoneal SL also improved volume regulation in the CHF rats, but only after 3 wk of treatment. Four weeks of SL treatment, either intracerebroventricularly or intraperitoneally, ameliorated both the increase in sympathetic drive and the impaired baroreflex function observed in VEH-treated CHF rats. These findings suggest that activation of MC receptors in the central nervous system plays a critical role in the altered volume regulation and augmented sympathetic drive that characterize clinical heart failure.

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Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.1.h317 ◽

1999 ◽

Vol 276 (1) ◽

pp. H317-H325 ◽

Cited By ~ 26

Author(s):

Frans H. H. Leenen ◽

Vaclav Skarda ◽

Baoxue Yuan ◽

Roselyn White

Keyword(s):

Coronary Artery ◽

Ace Inhibitors ◽

Time Course ◽

Cardiac Tissue ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Ang Ii ◽

Artery Ligation ◽

Conscious Rats ◽

Postmyocardial Infarction

We evaluated in rats the time course of changes in cardiac versus plasma ANG I and II postmyocardial infarction (MI) and the effects of nephrectomy and angiotensin-converting enzyme (ACE) inhibitors on the early changes post-MI. Acute coronary artery ligation was induced in conscious rats using the two-stage model, and plasma and cardiac tissue were obtained shortly (6 h, 1 and 3 days) and chronically (1, 4, and 8–9 wk) after MI. In an additional group of rats, bilateral nephrectomy was performed 18 h before the coronary artery ligation, and samples were obtained at 6 h post-MI. Furthermore, in two additional groups of rats, treatment with enalapril and quinapril was started 3 days before the ligation, and samples were obtained at 1 or 3 days post-MI. In these groups of rats, plasma and left ventricular (LV) (infarct and infarct free) ANG I and II were measured by RIA after separation on HPLC. In control rats, plasma ANG I and II showed a clear increase at 6 h post-MI but subsequently only minor increases were observed. In contrast, LV ANG II showed major increases at 6 h and 1 day post-MI, which had returned to normal by 3 days in the infarct-free LV and after 1(–2) wk in the infarct LV. LV ANG I showed a more gradual increase and remained elevated in the infarct up to 8–9 wk. Nephrectomy preceding the MI lowered ANG I and II in plasma but enhanced their increases in the heart at 6 h post-MI. Both ACE inhibitors decreased plasma ANG II associated with large increases in plasma ANG I. They also inhibited the increases in LV ANG II in both the infarct and infarct-free LV at 1 and 3 days post-MI with however no significant increase in LV ANG I. In conclusion, induction of a MI in conscious rats leads to rapid and marked, but only short-lived, increases in cardiac tissue ANG II in both the infarct and infarct-free parts of the LV. Pretreatment with ACE inhibitors, but not nephrectomy, blocks this increase. Local production appears to play a major role in the increases in cardiac ANG II post-MI.

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Ventricular arrhythmias in acute coronary artery ligation in dogs: Electrophysiological mechanism and its relation to the severity of myocardial ischemia.

Japanese Circulation Journal ◽

10.1253/jcj.45.517 ◽

1981 ◽

Vol 45 (4) ◽

pp. 517-523 ◽

Cited By ~ 3

Author(s):

SATOSHI OGAWA ◽

YOSHIRO NAKAMURA ◽

LEONARD S. DREIFUS ◽

ELIESER KAPLINSKY

Keyword(s):

Coronary Artery ◽

Myocardial Ischemia ◽

Ventricular Arrhythmias ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Electrophysiological Mechanism

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Abstract P278: Fibroblast Growth Factor 21 Mediated Protection of Ischemic Myocardium

Circulation Research ◽

10.1161/res.109.suppl_1.ap278 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Shu Q Liu ◽

Brandon Tefft ◽

Alexei Kharitonenkov ◽

Yupeng Ren ◽

Li-Qun Zhang ◽

...

Keyword(s):

Growth Factor ◽

Myocardial Ischemia ◽

Fibroblast Growth Factor ◽

Protein Level ◽

Volume Fraction ◽

Secretory Protein ◽

Fibroblast Growth Factor 21 ◽

Coronary Artery Ligation ◽

Fibroblast Growth ◽

Artery Ligation

Myocardial ischemia is a prevalent disorder causing heart failure. As cardiomyocyte death is the principal cause of cardiac functional deficits, a recognized treatment is to minimize cardiomyocyte death post myocardial ischemia. While extensive investigations have been conducted, few effective cardioprotective agents have been developed for clinical applications. The goal of this investigation is to test and establish a cardioprotective agent based on fibroblast growth factor 21 (FGF21), a secretory protein participating in innate cardioprotective responses. In myocardial ischemia induced by LAD coronary artery ligation in the mouse, hepatocytes upregulated FGF21 mRNA by 11 folds at 12 hrs, followed by an increase in the FGF21 protein level in hepatocytes and the serum. Administration of recombinant FGF21 to mice immediately post MI (50 ng/gm, IV, twice/day for 3 days) resulted in a significant reduction in the fraction of myocardial infarction (MI) with reference to the LV wall volume below the LAD ligation (38+/−5 and 21+/−4%, n=7, vs. albumin administration 51+/−8 and 31+/−5%, n=6, at day 1 and 10, respectively, p<0.05 for both times) in association with improved LV dp/dt. In FGF21 overexpressing mice, the volume fraction of MI (36+/−6%, n=6) was significantly lower than that in wildtype mice (48+/−6%, n=5, p<0.05) at day 1 post MI. Furthermore, FGF21 administration to normal mice induced phosphorylation of FGFR1, PI3K, Akt, and BAD in cardiomyocytes within 10 – 30 min. These molecules were also phosphorylated in cardiomyocytes within 1 day post MI. Injection of siRNA specific to FGFR1, PI3K, or Akt to the LV anterior wall at 6 locations about 2 mm apart (diffusion range of FITC-siRNA tested by fluorescence microscopy) 3 days prior to MI resulted in a reduction in the protein level of FGFR1, PI3K, or Akt by 65+/−9, 71+/−11, or 68+/−12%, respectively (n=3), within the region of siRNA injection at 1 day post MI in association with a reduction in BAD phosphorylation and an increase in the fraction of MI by 9+/−3, 8+/−2, or 11+/−3%, respectively (n=3). These observations suggested that FGF21 contributed to myocardial protection possibly via the FGFR1-PI3K-Akt-BAD signaling mechanisms and recombinant FGF21 may be potentially used as a cardioprotective agent.

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Differential Effects of Propofol and Sevoflurane on Ischemia-induced Ventricular Arrhythmias and Phosphorylated Connexin 43 Protein in Rats

Anesthesiology ◽

10.1097/aln.0b013e318190b537 ◽

2009 ◽

Vol 110 (1) ◽

pp. 50-57 ◽

Cited By ~ 18

Author(s):

Naoyuki Hirata ◽

Noriaki Kanaya ◽

Noriko Kamada ◽

Saori Kimura ◽

Akiyoshi Namiki

Keyword(s):

Coronary Artery ◽

Survival Rate ◽

Myocardial Ischemia ◽

Ventricular Arrhythmias ◽

Connexin 43 ◽

Acute Myocardial Ischemia ◽

High Dose ◽

Coronary Artery Ligation ◽

Sodium Pentobarbital ◽

Artery Ligation

Background The effects of anesthetics on ischemia-induced ventricular arrhythmias remain poorly studied. This study investigated the effects of propofol and sevoflurane on the survival rate and morbidity as a result of ventricular arrhythmias, and defined a possible mechanism for the arrhythmogenic properties of anesthetics during acute myocardial ischemia. Methods Under anesthesia with intraperitoneal sodium pentobarbital, Sprague-Dawley rats underwent 30 min of left anterior descending coronary artery ligation. The rats were divided into a low-dose propofol (Prop-LD) group (39 mg X kg(-1) X hr(-1), n = 18), a high-dose propofol group (78 mg x kg(-1) x hr(-1), n = 18), a sevoflurane group (2.5%, n = 18) and a control group (n = 18). The survival rate and morbidity as a result of ventricular arrhythmias were determined, and the amount of phosphorylated connexin 43 protein was measured 30 min after coronary artery ligation. Results The survival rate was 83% (15 of 18), 94% (17 of 18), 89% (16 of 18), and 67% (12 of 18, P = 0.038 vs. Prop-LD) in the control, Prop-LD, high-dose propofol, and sevoflurane groups, respectively. Sustained ventricular tachycardia was observed in 83% (15 of 18), 39% (7 of 18, P = 0.011 vs. control), 50% (9 of 18, P = 0.039 vs. control) and 94% (17 of 18, P < 0.01 vs. Prop-LD) in the control, Prop-LD, high-dose propofol, and sevoflurane groups, respectively. Immunoblotting showed a marked reduction in the amount of phosphorylated connexin 43 in the control and sevoflurane groups, as compared with the Prop-LD and high-dose propofol groups (P < 0.05). Conclusion The authors' results suggest that propofol preserves connexin 43 phosphorylation during acute myocardial ischemia, as compared with sevoflurane, and this might protect the heart from serious ventricular arrhythmias during acute coronary occlusion.

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