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Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition.

ABSTRACT: Myocardial infarction (MI), which is characterized by chamber dilation and LV dysfunction, is associated with substantially higher mortality. We investigated the effects and underlying mechanisms of Luteolin on post-infarction cardiac dysfunction. Myocardial infarction was constructed by left anterior descending coronary artery ligation. In vitro, cultured neonatal cardiomyocytes subjected to simulated MI were used to probe mechanism. Luteolin significantly improved cardiac function, decreased cardiac enzyme and inflammatory cytokines release after MI. Enhanced autophagic flux as indicated by more autophagosomes puncta, less accumulation of aggresomes and P62 in the neonatal cardiomyocytes after hypoxia was observed in the Luteolin pre-treatment group. Western blot analysis also demonstrated that Luteolin up-regulated autophagy in the cardiomyocytes subjected to simulated MI injury. Furthermore, Luteolin increased mitochondrial membrane potential, adenosine triphosphate content, citrate synthase activity and complexes I/II/III/IV/V activities in the cardiomyocytes subjected to simulated MI injury. Interestingly, mammalian sterile 20-like kinase 1 (Mst1) knockout abolished the protective effects of Luteolin administration. Luteolin enhances cardiac function, reduces cardiac enzyme and inflammatory markers release after MI. The protective effects of Luteolin are associated with up-regulation of autophagy and improvement of mitochondrial biogenesis through Mst1 inhibition.

SUBMITTER: Hu J

PROVIDER: S-EPMC4717847 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition.

Hu Jianqiang J Man Wanrong W Shen Min M Zhang Mingming M Lin Jie J Wang Tingting T Duan Yu Y Li Congye C Zhang Rongqing R Gao Erhe E Wang Haichang H Sun Dongdong D

Journal of cellular and molecular medicine 20151105 1

Myocardial infarction (MI), which is characterized by chamber dilation and LV dysfunction, is associated with substantially higher mortality. We investigated the effects and underlying mechanisms of Luteolin on post-infarction cardiac dysfunction. Myocardial infarction was constructed by left anterior descending coronary artery ligation. In vitro, cultured neonatal cardiomyocytes subjected to simulated MI were used to probe mechanism. Luteolin significantly improved cardiac function, decreased c ...[more]

PMID: 26538370

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Project description:Matrix metalloproteinase-9 (MMP-9) is robustly elevated in the first week post-myocardial infarction (MI). Targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-MI by reducing macrophage infiltration and collagen accumulation through increased apoptosis and reduced inflammation. In this study, we used a translational experimental design to determine whether selective MMP-9 inhibition early post-MI would be an effective therapeutic strategy in mice. We enrolled male C57BL/6J mice (3-6months old, n=116) for this study. Mice were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03μg/day) treatment was initiated at 3h post-MI and the mice were sacrificed at day (D) 1 or 7 post-MI. MMP-9i reduced MMP-9 activity by 31±1% at D1 post-MI (p<0.05 vs saline) and did not affect survival or infarct area. Surprisingly, MMP-9i treatment increased infarct wall thinning and worsened cardiac function at D7 post-MI. While MMP-9i enhanced neutrophil infiltration at D1 and macrophage infiltration at D7 post-MI, CD36 levels were lower in MMP-9i compared to saline, signifying reduced phagocytic potential per macrophage. Escalation and prolongation of the inflammatory response at D7 post-MI in the MMP-9i group was evident by increased expression of 18 pro-inflammatory cytokines (all p<0.05). MMP-9i reduced cleaved caspase 3 levels at D7 post-MI, consistent with reduced apoptosis and defective inflammation resolution. Because MMP-9i effects on inflammatory cells were significantly different from previously observed MMP-9 null mechanisms, we evaluated pre-MI (baseline) systemic differences between C57BL/6J and MMP-9 null plasma. By mass spectrometry, 34 plasma proteins were significantly different between groups, revealing a previously unappreciated altered baseline environment pre-MI when MMP-9 was deleted. In conclusion, early MMP-9 inhibition delayed inflammation resolution and exacerbated cardiac dysfunction, highlighting the importance of using translational approaches in mice.

Dataset Information

Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition.

Publications

Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition.

Similar Datasets

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