Intestinal Microbial Metabolites Are Linked to Severity of Myocardial Infarction in Rats.

Intestinal microbiota determine severity of myocardial infarction in rats. We determined whether low molecular weight metabolites derived from intestinal microbiota and transported to the systemic circulation are linked to severity of myocardial infarction. Plasma from rats treated for seven days with the non-absorbed antibiotic vancomycin or a mixture of streptomycin, neomycin, polymyxin B and bacitracin was analyzed using mass spectrometry-based metabolite profiling platforms.

Thrombopoietin receptor agonists protect human cardiac myocytes from injury by activation of cell survival pathways.

Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart. Eltrombopag is a small molecule agonist of the thrombopoietin receptor, the physiologic target of thrombopoietin. However, the ability of eltrombopag and thrombopoietin to protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known.

Cardiac injury after 10 gy total body irradiation: indirect role of effects on abdominal organs.

The objective of this study was to determine whether radiation-induced injury to the heart after 10 Gy total body irradiation (TBI) is direct or indirect. Young male WAG/RijCmcr rats received a 10 Gy single dose using TBI, upper hemi-body (UHB) irradiation, lower hemi-body (LHB) irradiation, TBI with the kidneys shielded or LHB irradiation with the intestines shielded. Age-matched, sham-irradiated rats served as controls.

Heparin oligosaccharides inhibit chemokine (CXC motif) ligand 12 (CXCL12) cardioprotection by binding orthogonal to the dimerization interface, promoting oligomerization, and competing with the chemokine (CXC motif) receptor 4 (CXCR4) N terminus.

The ability to interact with cell surface glycosaminoglycans (GAGs) is essential to the cell migration properties of chemokines, but association with soluble GAGs induces the oligomerization of most chemokines including CXCL12. Monomeric CXCL12, but not dimeric CXCL12, is cardioprotective in a number of experimental models of cardiac ischemia. We found that co-administration of heparin, a common treatment for myocardial infarction, abrogated the protective effect of CXCL12 in an ex vivo rat heart model for myocardial infarction.

Intestinal microbiota determine severity of myocardial infarction in rats.

Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infarcts (27% reduction), and improved recovery of postischemic mechanical function (35%) as compared with untreated controls.

10 Gy total body irradiation increases risk of coronary sclerosis, degeneration of heart structure and function in a rat model.

Purpose: To determine the impact of 10 Gy total body irradiation (TBI) or local thorax irradiation, a dose relevant to a radiological terrorist threat, on lipid and liver profile, coronary microvasculature and ventricular function.

Materials And Methods: WAG/RijCmcr rats received 10 Gy TBI followed by bone marrow transplantation, or 10 Gy local thorax irradiation. Age-matched, non-irradiated rats served as controls.

Monomeric structure of the cardioprotective chemokine SDF-1/CXCL12.

The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) directs leukocyte migration, stem cell homing, and cancer metastasis through activation of CXCR4, which is also a coreceptor for T-tropic HIV-1. Recently, SDF-1 was shown to play a protective role after myocardial infarction, and the protein is a candidate for development of new anti-ischemic compounds. SDF-1 is monomeric at nanomolar concentrations but binding partners promote self-association at higher concentrations to form a typical CXC chemokine homodimer.

Parstatin: a cryptic peptide involved in cardioprotection after ischaemia and reperfusion injury.

Aims: Thrombin activates protease-activated receptor 1 by proteolytic cleavage of the N-terminus. Although much research has focused on the activated receptor, little is known about the 41-amino acid N-terminal peptide (parstatin). We hypothesized that parstatin would protect the heart against ischaemia-reperfusion injury.

Gadolinium limits myocardial infarction in the rat: dose-response, temporal relations and mechanisms.

The lanthanide cation, gadolinium (Gd) attenuates post-ischemic myocardial stunning. This study tests the hypothesis that Gd also preconditions the myocardium against infarction following ischemia-reperfusion (IR) and explores potential mechanisms underlying Gd-induced cardioprotection. Regional myocardial infarction was induced in rats by occluding the left anterior descending artery for 30 min and reperfusing for 120 min.

Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signaling.

Harnessing endogenous cardioprotectants is a novel therapeutic strategy to combat ischemia/reperfusion (I/R) injury. Thrombin causes I/R injury, whereas exogenous adenosine prevents I/R injury. We hypothesized that blocking thrombin receptor activation with a protease-activated receptor (PAR) 4 antagonist would unmask the cardioprotective effects of endogenous adenosine.

Mitochondrial big conductance KCa channel and cardioprotection in infant rabbit heart.

Chronic hypoxia increases resistance to myocardial ischemia in infants. Activation of the mitochondrial big conductance Ca(2+) -sensitive K channel (mitoBKCa) has been shown to be protective in adult hearts; however, its role in infant hearts is unknown. Hearts from normoxic or hypoxic infant rabbits were perfused with a mitoKCa opener, NS1619, or blocker Paxilline before ischemia and reperfusion.

Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats.

Aims: Thrombopoietin (Tpo) is known for its ability to stimulate platelet production. However, it is currently unknown whether Tpo plays a physiological function in the heart.

Methods And Results: We assessed the potential protective role of Tpo in vitro and in vivo in two rat models of myocardial ischaemia/reperfusion.

Nitrite confers protection against myocardial infarction: role of xanthine oxidoreductase, NADPH oxidase and K(ATP) channels.

Reduction of nitrite to nitric oxide during ischemia protects the heart against injury from ischemia/reperfusion. However the optimal dose of nitrite and the mechanisms underlying nitrite-induced cardioprotection are not known. We determined the ability of nitrite and nitrate to confer protection against myocardial infarction in two rat models of ischemia/reperfusion injury and the role of xanthine oxidoreductase, NADPH oxidase, nitric oxide synthase and K(ATP) channels in mediating nitrite-induced cardioprotection.

SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts.

Myocardial ischemia/reperfusion (I/R) injury is partly mediated by thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R. Several cellular responses to thrombin are mediated by a G-protein coupled protease-activated receptor 1 (PAR1).

Hyperoxic and hyperbaric-induced cardioprotection: role of nitric oxide synthase 3.

Objective: The relative contributions of the fraction of inspired oxygen (FIO2) and atmospheric pressure (ATM) to cardioprotection are unknown. We determined whether the product of FIO2 x ATM (oxygen partial pressure) controls the extent of hyperoxic+hyperbaric-induced cardioprotection and involves activation of nitric oxide synthase (NOS).

Methods: Adult Sprague Dawley rats (n = 10/gp) were treated for 1 h with (1) normoxia+normobaria (21% O2 at 1 ATM), (2) hyperoxia+normobaria (100% O2 at 1 ATM), (3) normoxia+hyperbaria (21% O2 at 2 ATM) and (4) hyperoxia+hyperbaria (100% O2 at 2 ATM).

Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways.

The immediate protective effect of erythropoietin (EPO) against ischemia in heart suggests a role beyond hematopoiesis and the treatment of anemia. We determined the role of JAK/STAT and Ras/Rac/MAPK in the protective effect of EPO against ischemia-reperfusion injury in infant rabbit heart. EPO (1.

Delayed cardioprotection with isoflurane: role of reactive oxygen and nitrogen.

We determined whether isoflurane can confer delayed cardioprotection in the adult rat by triggering increased production of reactive oxygen (ROS) and nitrogen species (RNS). Our objectives were to determine 1) the concentration of isoflurane that confers delayed cardioprotection in the adult rat, 2) the role of ROS and RNS in the induction of delayed cardioprotection, and 3) the cellular sources of ROS and RNS responsible for induction of delayed cardioprotection by isoflurane. Male Sprague-Dawley rats at 8 wk of age (n = 8 rats/group) were exposed to 0.

Cardioprotection in chronically hypoxic rabbits persists on exposure to normoxia: role of NOS and KATP channels.

Hypoxia from birth increases resistance to myocardial ischemia in infant rabbits. We hypothesized that increased cardioprotection in hearts chronically hypoxic from birth persists following development in a normoxic environment and involves increased activation of nitric oxide synthase (NOS) and ATP-dependent K (K(ATP)) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic (Fi(O(2)) = 0.

Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels.

Erythropoietin is protective against cardiac ischemia, but the underlying mechanisms are unknown. We determined whether erythropoietin (0.5 - 10.

Chronic hypoxia increases endothelial nitric oxide synthase generation of nitric oxide by increasing heat shock protein 90 association and serine phosphorylation.

Chronic hypoxia increases endothelial nitric oxide synthase (eNOS) production of nitric oxide (*NO) and cardioprotection in neonatal rabbit hearts. However, the mechanism by which this occurs remains unclear. Recent studies suggest that heat shock protein 90 (hsp90) alters eNOS function.

Activation of protein kinases in chronically hypoxic infant human and rabbit hearts: role in cardioprotection.

Background: Many infants who undergo heart surgery have a congenital cyanotic defect in which the heart is chronically perfused with hypoxic blood. However, the signaling pathways by which infant hearts adapt to chronic hypoxia and resist subsequent surgical ischemia is unknown.

Methods And Results: We determined the activation and translocation of protein kinase C (PKC) isoforms and mitogen activated protein kinases (MAP kinases) in 15 infants with cyanotic (SaO2<85%) or acyanotic (SaO2>95%) heart defects undergoing surgical repair and in 80 rabbits raised from birth in a hypoxic (SaO2<85%) or normoxic (SaO2>95%) environment.