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Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity.

ABSTRACT: Oncostatin M (OSM) exhibits many unique biological activities by activating O? receptor. However, its role in myocardial I/R injury in diabetic mice remains unknown. The involvement of OSM was assessed in diabetic mice which underwent myocardial I/R injury by OSM treatment or genetic deficiency of OSM receptor O?. Its mechanism on cardiomyocyte apoptosis, mitochondrial biogenesis and insulin sensitivity were further studied. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through inhibition of inositol pyrophosphate 7 (IP7) production, thus activating PI3K/Akt/BAD pathway, decreasing Bax expression while up-regulating Bcl-2 expression and decreasing the ratio of Bax to Bcl-2 in db/db mice. OSM enhanced mitochondrial biogenesis and mitochondrial function in db/db mice subjected to cardiac I/R injury. On the contrary, OSM receptor O? knockout exacerbated cardiac I/R injury, increased IP7 production, enhanced cardiomyocyte apoptosis, impaired mitochondrial biogenesis, glucose homoeostasis and insulin sensitivity in cardiac I/R injured diabetic mice. Inhibition of IP7 production by TNP (IP6K inhibitor) exerted similar effects of OSM. The mechanism of OSM on cardiac I/R injury in diabetic mice is partly associated with IP7/Akt and adenine mononucleotide protein kinase/PGC-1? pathway. OSM protects against cardiac I/R Injury by regulating apoptosis, insulin sensitivity and mitochondrial biogenesis in diabetic mice through inhibition of IP7 production.

SUBMITTER: Sun D

PROVIDER: S-EPMC4459845 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity.

Sun Dongdong D Li Shuang S Wu Hao H Zhang Mingming M Zhang Xiaotian X Wei Liping L Qin Xing X Gao Erhe E

Journal of cellular and molecular medicine 20150308 6

Oncostatin M (OSM) exhibits many unique biological activities by activating Oβ receptor. However, its role in myocardial I/R injury in diabetic mice remains unknown. The involvement of OSM was assessed in diabetic mice which underwent myocardial I/R injury by OSM treatment or genetic deficiency of OSM receptor Oβ. Its mechanism on cardiomyocyte apoptosis, mitochondrial biogenesis and insulin sensitivity were further studied. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis ...[more]

PMID: 25752217

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Project description:AimsNo effective therapy is available in clinics to protect the heart from ischaemia/reperfusion (I/R) injury. Endothelial cells are activated after I/R, which may drive the inflammatory response by releasing ATP through pannexin1 (Panx1) channels. Here, we investigated the role of Panx1 in cardiac I/R.Methods and resultsPanx1 was found in cardiac endothelial cells, neutrophils, and cardiomyocytes. After in vivo I/R, serum Troponin-I, and infarct size were less pronounced in Panx1-/- mice, but leukocyte infiltration in the infarct area was similar between Panx1-/- and wild-type mice. Serum Troponin-I and infarct size were not different between mice with neutrophil-specific deletion of Panx1 and Panx1fl/fl mice, suggesting that cardioprotection by Panx1 deletion rather involved cardiomyocytes than the inflammatory response. Physiological cardiac function in wild-type and Panx1-/- hearts was similar. The time to onset of contracture and time to maximal contracture were delayed in Panx1-/- hearts, suggesting reduced sensitivity of these hearts to ischaemic injury. Moreover, Panx1-/- hearts showed better recovery of left ventricle developed pressure, cardiac contractility, and relaxation after I/R. Ischaemic preconditioning failed to confer further protection in Panx1-/- hearts. Panx1 was found in subsarcolemmal mitochondria (SSM). SSM in WT or Panx1-/- hearts showed no differences in morphology. The function of the mitochondrial permeability transition pore and production of reactive oxygen species in SSM was not affected, but mitochondrial respiration was reduced in Panx1-/- SSM. Finally, Panx1-/- cardiomyocytes had a decreased mitochondrial membrane potential and an increased mitochondrial ATP content.ConclusionPanx1-/- mice display decreased sensitivity to cardiac I/R injury, resulting in smaller infarcts and improved recovery of left ventricular function. This cardioprotective effect of Panx1 deletion seems to involve cardiac mitochondria rather than a reduced inflammatory response. Thus, Panx1 may represent a new target for controlling cardiac reperfusion damage.

Project description:BackgroundMitochondrial dysfunction is considered to be an important contributor in podocyte injury under diabetic conditions. The BaoShenTongLuo (BSTL) formula has been shown to reduce podocyte damage and postpone the progression of diabetic kidney disease (DKD). The potential mechanisms underlying the effects of BSTL, however, have yet to be elucidated. In this study, we aimed to investigate whether the effects of BSTL are related to the regulation of mitochondrial biogenesis via the adenosine monophosphate-activated protein kinase (AMPK) pathway.MethodsHigh-Performance Liquid Chromatography Electrospray Ionization Mass Spectrometer (HPLC-ESI-MS) analysis was performed to investigate the characteristics of pure compounds in BSTL. db/db mice and mouse podocyte clone-5 (MPC5) cells were exposed to high glucose (HG) to induce DKD and podocyte damage. Body weight, random blood glucose, urinary albumin/creatinine ratio (UACR), indicators of renal function and renal histological lesions were measured. Markers of podocyte injury, mitochondrial morphology, mitochondrial deoxyribonucleic acid (mtDNA) content, mitochondrial respiratory chain complexes activities, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) levels were assessed. Protein expressions of AMPK, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), transcription factor A (TFAM), mitochondrial fusion protein 2 (MFN2) and dynamin-related protein 1 (DRP1) were also detected. MPC5 cells were transfected with AMPKα small interfering RNA (AMPKα siRNA) to determine the underlying mechanisms of BSTL improvement of mitochondrial function under diabetic conditions.ResultsIn vivo, treatment with BSTL reduced the UACR levels, reversed the histopathological changes in renal tissues, and alleviated the podocyte injury observed in db/db mice. After BSTL treatment, the decreased mtDNA content and mitochondrial respiratory chain complex I, III, and IV activities were significantly improved, and these effects were accompanied by maintenance of the protein expression of p-AMPKαT172, PGC-1α, TFAM and MFN2. The in vitro experiments also showed that BSTL reduced podocyte apoptosis, suppressed excessive cellular ROS production, and reversed the decreased in MMP that were observed under HG conditions. More importantly, the effects of BSTL in enhancing mitochondrial biogenesis and reducing podocyte apoptosis were inhibited in AMPKα siRNA-treated podocytes.ConclusionBSTL plays a crucial role in protecting against podocyte injury by regulating the AMPK-mediated mitochondrial biogenesis in DKD.

Project description:AimsCardiac ischaemia/reperfusion (I/R) injury remains a critical issue in the therapeutic management of ischaemic heart failure. Although mild hypothermia has a protective effect on cardiac I/R injury, more rapid and safe methods that can obtain similar results to hypothermia therapy are required. 2-Methyl-2-thiazoline (2MT), an innate fear inducer, causes mild hypothermia resulting in resistance to critical hypoxia in cutaneous or cerebral I/R injury. The aim of this study is to demonstrate the protective effect of systemically administered 2MT on cardiac I/R injury and to elucidate the mechanism underlying this effect.Methods and resultsA single subcutaneous injection of 2MT (50 mg/kg) was given prior to reperfusion of the I/R injured 10 week-old male mouse heart and its efficacy was evaluated 24 h after the ligation of the left anterior descending coronary artery. 2MT preserved left ventricular systolic function following I/R injury (ejection fraction, %: control 37.9 ± 6.7, 2MT 54.1 ± 6.4, P < 0.01). 2MT also decreased infarct size (infarct size/ischaemic area at risk, %: control 48.3 ± 12.1, 2MT 25.6 ± 4.2, P < 0.05) and serum cardiac troponin levels (ng/mL: control 8.9 ± 1.1, 2MT 1.9 ± 0.1, P < 0.01) after I/R. Moreover, 2MT reduced the oxidative stress-exposed area within the heart (%: control 25.3 ± 4.7, 2MT 10.8 ± 1.4, P < 0.01). These results were supported by microarray analysis of the mouse hearts. 2MT induced a transient, mild decrease in core body temperature (°C: -2.4 ± 1.4), which gradually recovered over several hours. Metabolome analysis of the mouse hearts suggested that 2MT minimized energy metabolism towards suppressing oxidative stress. Furthermore, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography imaging revealed that 2MT reduced the activity of brown adipose tissue (standardized uptake value: control 24.3 ± 6.4, 2MT 18.4 ± 5.8, P < 0.05). 2MT also inhibited mitochondrial respiration and glycolysis in rat cardiomyoblasts.ConclusionsWe identified the cardioprotective effect of systemically administered 2MT on cardiac I/R injury by sparing energy metabolism with reversible hypothermia. Our results highlight the potential of drug-induced hypothermia therapy as an adjunct to coronary intervention in severe ischaemic heart disease.

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Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity.

Publications

Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity.

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