Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury.

Abstract

Oncostatin M (OSM) exhibits many unique biological activities by activating the Oβ receptor. However, its role in myocardial ischemia/reperfusion injury (I/R injury) in mice remains unknown. We investigated whether Notch3/Akt signaling is involved in the regulation of OSM-induced protection against cardiac I/R injury. The effects of OSM were assessed in mice that underwent myocardial I/R injury by OSM treatment or by genetic deficiency of the OSM receptor Oβ. We investigated its effects on cardiomyocyte apoptosis and mitochondrial biogenesis and whether Notch3/Akt signaling was involved in the regulation of OSM-induced protection against cardiac I/R injury. The mice underwent 30 min of ischemia followed by 3 h of reperfusion and were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) 72 h before coronary artery ligation. Myocardial infarct size, cardiac function, cardiomyocyte apoptosis and mitochondria morphology in mice that underwent cardiac I/R injury were compared between groups. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through promotion of Notch3 production, thus activating the PI3K/Akt pathway. OSM enhanced mitochondrial biogenesis and mitochondrial function in mice subjected to cardiac I/R injury. In contrast, OSM receptor Oβ knock out exacerbated cardiac I/R injury, decreased Notch3 production, enhanced cardiomyocyte apoptosis, and impaired mitochondrial biogenesis in cardiac I/R injured mice. The mechanism of OSM on cardiac I/R injury is partly mediated by the Notch3/Akt pathway. These results suggest a novel role of Notch3/Akt signaling that contributes to OSM-induced protection against cardiac I/R injury.

• Authors: Mingming Zhang, Chen Wang, Jianqiang Hu, Jie Lin, Zhijing Zhao, Min Shen, Haokao Gao, Na Li, Min Liu, Pengfei Zheng, Cuiting Qiu, Erhe Gao, Haichang Wang, Dongdong Sun
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 20 Issue 9 Pg. 1150-63 (Sep 2015) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 26093524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Growth Inhibitors
• Notch3 protein, mouse
• RNA, Small Interfering
• Receptor, Notch3
• Receptors, Notch
• Receptors, Oncostatin M
• Oncostatin M
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Growth Inhibitors (pharmacology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondria (drug effects)
• Myocardial Infarction (metabolism)
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Myocytes, Cardiac
• Oncostatin M (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (metabolism)
• Rats
• Receptor, Notch3
• Receptors, Notch (metabolism)
• Receptors, Oncostatin M (genetics, metabolism)
• Signal Transduction (drug effects)