minocycline and Myocardial-Ischemia

Apoptosis, a genetically programmed form of cell death, contributes to myocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. The apoptotic program is complex, involving both pro- and anti-apoptotic proteins, and apoptosis occurs when the equilibrium between these opposing factors is perturbed. Some of these factors are intrinsic to the apoptotic pathway, such as the pro- and anti-apoptotic members of the Bcl2 family. Other, extrinsic, cellular factors can also modify the outcome of the response to an apoptotic stimulus. In this review, we have focused on some of these extrinsic factors, such as STAT-1 as a pro-apoptotic agent and the urocortins and Bag-1 as anti-apoptotic factors, since these may be potential therapeutic targets. In addition, we discuss the profound cytoprotective effects of the antibiotic, minocycline.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Cardiotonic Agents; Corticotropin-Releasing Hormone; Humans; Ischemic Preconditioning, Myocardial; Minocycline; Mitochondrial Proteins; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Necrosis; STAT Transcription Factors; Urocortins

Preclinical studies indicate that minocycline protects against myocardial ischemia/reperfusion injury. In these studies, minocycline was administered before ischemia, which can rarely occur in clinical practice. The current study aimed to evaluate cardioprotection by minocycline treatment upon reperfusion.. Rabbits were subjected to myocardial ischemia/reperfusion injury and received either intravenous minocycline (n = 8) or saline (n = 8) upon reperfusion. Cardiac cell death was assessed by in vivo micro-SPECT/CT after injection of Indium-111-labeled 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (. Myocardial damage was visualized by micro-SPECT/CT imaging. Quantitative GSAO uptake (expressed as percent injected dose per gram, %ID/g) in the area at risk was lower in minocycline-treated animals than that in saline-treated control animals (0.32 ± 0.13% vs 0.48 ± 0.15%, P = 0.04). TUNEL staining confirmed the reduction of cell death in minocycline-treated animals.. This study demonstrates cardioprotection by minocycline in a clinically translatable protocol.

Topics: Animals; Arsenicals; Cell Death; Disease Models, Animal; Glutathione; Heart; Indium Radioisotopes; Minocycline; Multimodal Imaging; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rabbits; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

Minocycline has been shown to protect against myocardial ischemia-reperfusion injury. This study investigated the effects of minocycline on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with minocycline (45mg/kg, i.p.) 1h before ischemia in the absence and/or presence of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002, 0.3mg/kg, i.v., a PI3K inhibitor) and 5-hydroxydecanoic acid [5-HD, 10mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium (K(ATP)) channels] which were once injected 10min before ischemia and then subjected to ischemia for 30min. Ventricular arrhythmias were assessed. L-type Ca(2+) current was measured by the patch-clamp technique. During the 30-minute ischemia, minocycline significantly reduced the incidence of ventricular fibrillation (VF) (P<0.05). The duration of VT+VF, the number of VT+VF episodes and the severity of arrhythmias were all significantly reduced by minocycline compared to those in myocardial ischemia group (P<0.05 for all). Administration of LY294002 or 5-HD abolished the protective effects of minocycline on VF incidence, the duration of VT+VF, the number of VT+VF episodes and the severity of arrhythmias (P<0.05 for all). In addition, minocycline inhibited L-type Ca(2+) currents of normal myocardial cell membrane in a dose-dependent manner. This study suggested that minocycline could attenuate ischemia-induced ventricular arrhythmias in rats in which PI3K/Akt signaling pathway, mitochondrial K(ATP) channels and L-type Ca(2+) channels may be involved.

Topics: Animals; Anti-Bacterial Agents; Arrhythmias, Cardiac; Calcium; Cell Membrane; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Male; Minocycline; Myocardial Ischemia; Phosphatidylinositol 3-Kinases; Phosphoproteins; Potassium Channels; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction

Minocycline has been shown to protect against myocardial ischemia and reperfusion injury. However, the mechanism remains unclear. This study was to investigate the role of high mobility group box 1 protein (HMGB1) in the cardioprotection of minocycline during myocardial ischemia and reperfusion in rats. Anesthetized male rats were once treated with minocycline (45 mg/kg, i.p.) 1h before ischemia, and then subjected to ischemia for 30 min followed by reperfusion for 4h. The lactate dehydrogenase (LDH), creatine kinase (CK) and infarct size were measured and the myocardial tissue apoptosis was assessed by TUNNEL assay. Neonatal rat ventricular myocytes were prepared and then cultured with recombinant HMGB1. Cell apoptosis was measured using an annexin V-FITC apoptosis detection kit. HMGB1 expression was assessed by immunoblotting. After 4h of reperfusion, minocycline could significantly decrease the infarct size, myocardium apoptosis and the levels of LDH and CK (all P<0.05). Meanwhile, minocycline could also significantly inhibit the HMGB1 expression during myocardial ischemia and reperfusion compared to that in ischemia and reperfusion group (P<0.05). In vitro, HMGB1 could significantly decrease the cell viability and promote the apoptosis of neonatal myocytes in a dose-dependent manner. The present study suggested that minocycline could protect against myocardial ischemia and reperfusion injury by inhibiting HMGB1 expression.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Survival; Cells, Cultured; Creatine Kinase; Disease Models, Animal; Gene Expression Regulation; HMGB1 Protein; L-Lactate Dehydrogenase; Male; Malondialdehyde; Minocycline; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

This study is aimed at investigating the novel use of minocycline for cardiac protection during ischemia/reperfusion (I/R) injury, as well as its mechanism of action.. Minocycline is a tetracycline with anti-inflammatory properties, which is used clinically for the treatment of diseases such as urethritis and rheumatoid arthritis. Experimentally, minocycline has also been shown to be neuroprotective in animal models of cerebral ischemia and to delay progression and improve survival in mouse models of neurodegenerative diseases.. We studied 62 rat intact hearts exposed to I/R and cell cultures of neonatal and adult rat ventricular myocytes.. Minocycline significantly reduced necrotic and apoptotic cell death, both in neonatal and adult myocytes, not only when given prior to hypoxia (p < 0.001), but also at reoxygenation (p < 0.05). Moreover, in the intact heart exposed to I/R, in vivo treatment with minocycline promoted hemodynamic recovery (p < 0.001) and cell survival, with reduction of infarct size (p < 0.001), cardiac release of creatine phosphokinase (p < 0.001), and apoptotic cell death (p < 0.001). In regard to its antiapoptotic mechanism of action, minocycline significantly reduced the expression level of initiator caspases, increased the ratio of XIAP to Smac/DIABLO at both the messenger RNA and protein level, and prevented mitochondrial release of cytochrome c and Smac/DIABLO (all, p < 0.05). These synergistic actions dramatically prevent the post-ischemic induction of caspase activity associated with cardiac I/R injury.. Because of its safety record and multiple novel mechanisms of action, minocycline may be a valuable cardioprotective agent to ameliorate cardiac dysfunction and cell loss associated with I/R injury.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Apoptosis; Apoptosis Regulatory Proteins; Carrier Proteins; Caspase Inhibitors; Cells, Cultured; Cytochromes c; Down-Regulation; Enzyme Inhibitors; Minocycline; Mitochondria, Heart; Mitochondrial Proteins; Myocardial Infarction; Myocardial Ischemia; Myocytes, Cardiac; Oxygen; Proteins; Rats; Rats, Sprague-Dawley; Reperfusion Injury; X-Linked Inhibitor of Apoptosis Protein