Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian sterile 20-like kinase 1 (Mst1) is a critical component of the Hippo signaling pathway, which regulates a variety of biological processes ranging from cell contact inhibition, organ size control, apoptosis and tumor suppression in mammals. Mst1 plays essential roles in the heart disease since its activation causes cardiomyocyte apoptosis and dilated cardiomyopathy. However, the mechanism underlying Mst1 activation in the heart remains unknown. In a yeast two-hybrid screen of a human heart cDNA library with Mst1 as bait, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as an Mst1-interacting protein. The interaction of GAPDH with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK293 cells and mouse heart homogenates, in which GAPDH interacted with the kinase domain of Mst1, whereas the C-terminal catalytic domain of GAPDH mediated its interaction with Mst1. Moreover, interaction of Mst1 with GAPDH caused a robust phosphorylation of GAPDH and markedly increased the Mst1 activity in cells. Chelerythrine, a potent inducer of apoptosis, substantially increased the nuclear translocation and interaction of GAPDH and Mst1 in cardiomyocytes. Overexpression of GAPDH significantly augmented the Mst1 mediated apoptosis, whereas knockdown of GAPDH markedly attenuated the Mst1 activation and cardiomyocyte apoptosis in response to either chelerythrine or hypoxia/reoxygenation. These findings reveal a novel function of GAPDH in Mst1 activation and cardiomyocyte apoptosis and suggest that disruption of GAPDH interaction with Mst1 may prevent apoptosis related heart diseases such as heart failure and ischemic heart disease.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase interacts with proapoptotic kinase mst1 to promote cardiomyocyte apoptosis. 2352 7

Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of trans-Golgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.
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PMID:An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. 3066 75

This study aimed at investigating the effect and underlying mechanism of miR-139-5p in myocardial ischemia and reperfusion (I/R) injury. A hypoxia/ reoxygenation (H/R) model was established in H9c2 cardiomyocytes. The level of miR-139-5p was detected in H/R-treated cardiomyocytes, and subsequently, the level of miR-139-5p or its target gene autophagy-related 4D (ATG4D) was up- or downregulated. Furthermore, the cell viability, apoptosis, and autophagy, as well as the expression levels of the proteins related to adenosine 5'-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/uncoordinated 51-like kinase 1 (ULK1) signaling pathway were determined. The MiR-139-5p was downregulated in H/R-treated cardiomyocytes in comparison to the untreated cells (P < 0.05). H/R treatment significantly decreased the cell viability but increased the cell apoptosis ratio, and autophagy-related proteins levels (P < 0.05). The overexpression of MiR-139-5p significantly promoted cell apoptosis and inhibited cell autophagy induced by H/R (P < 0.05); however, the effects of miR-139-5p on cell apoptosis and cell autophagy were inhibited by its target gene ATG4D (P < 0.05). Furthermore, the upregulated miR-139-5p remarkably inhibited the expression of p-AMPK, p-Raptor, and ULK1, but increased that of p-mTOR (P < 0.05) in H/R-treated cardiomyocytes. The MiR-139-5p has the potential of regulating cell apoptosis and cell autophagy by inhibiting AMPK/mTOR/ULK1 signaling pathway and thereby protecting against myocardial I/R injury.
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PMID:MiR-139-5p protect against myocardial ischemia and reperfusion (I/R) injury by targeting autophagy-related 4D and inhibiting AMPK/mTOR/ULK1 pathway. 3196 6