Dataset Information

SPA-1 attenuate myocardial hypoxia and reoxygenation injury via regulating RAC1: an iTRAQ-based proteomic study

ABSTRACT: Previous studies indicated that the ras-related C3 botulinum toxin substrate 1 (RAC1), a member of the Rac family of guanosine triphosphate phosphohydrolases (GTPase), is an important regulator of myocardial ischemia and reperfusion (I/R) injury. Potential interaction between the signal-induced proliferation-associated 1 (SPA-1) and RAC1 has been observed in cancer and neurological diseases, but the role of SPA-1 in myocardial I/R injury has not been fully investigated. Using iTRAQ-based proteomic analysis, we found that SPA-1 protein expression was moderately upregulated and RAC1 was significantly activated in H9C2 cells treated with hypoxia and reoxygenation (H/R). Moreover, others have shown that inhibiting SPA-1 with siRNA and overexpressing SPA-1 with plasmid transfection moderately upregulated SPA-1 during H/R which may be protect against H/R related cardiomyocyte injury and subsequent cytoskeleton malformation, cardiac fibrosis, apoptosis, and cellular reactive oxygen species formation. Finally, in a rat model of myocardial I/R induced by left anterior descending artery ligation, adenovirus-mediated overexpression of SPA-1 significantly alleviated the pathohistological changes in the myocardium and inhibited RAC1 activation. Taken together, these results indicate that under I/R conditions, moderate upregulation of SPA-1 may be a self-regulated cardioprotective response against RAC1-mediated injuries via attenuating multiple pathophysiological processes. Targeted enhancing of SPA-1 protein expression and suppressing RAC1 activation may be an important treatment strategy for preventing myocardial I/R injury.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Yinglu Hao

PROVIDER: PXD015991 | iProX | Wed Oct 23 00:00:00 GMT+01:00 2019

REPOSITORIES: iProX

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Publications

MicroRNA‑194‑5p attenuates hypoxia/reoxygenation‑induced apoptosis in H9C2 cardiomyocytes by inhibiting the over‑activation of RAC1 protein.

Li Cuie C Li Yinghua Y Li Yanping Y Wang Yudi Y Teng Yirong Y Hao Yinglu Y

Molecular medicine reports 20221223 2

Ras‑related C3 botulinum toxin substrate 1 (RAC1), a member of the Rac family of guanosine triphosphate phosphohydrolases, has been suggested to be a regulator of myocardial injury during ischemia and reperfusion (I/R). Whether microRNAs (miRs) are involved in the regulation of the aforementioned process remains to be elucidated. In the present study, an <i>in vitro</i> model of H9C2 cardiomyocytes was used to establish the overexpression of RAC1 following hypoxia and reoxygenation (H/R). Overex ...[more]

PMID: 36562344

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Project description:Inflammatory response plays a bidirectional regulatory role in myocardial infarction (MI). TLR signaling pathway plays an important role in the development of inflammation. Additionally, we discovered that CCRR is an anti-arrhythmic lncRNA in a prior work. Here we show, it is decreased in mice with 3-day MI followed by a sharp increase of pro-inflammatory cytokines and activation of the TLR pathway. Overexpression of CCRR could effectively inhibit the inflammatory response, reduce the infarct area, and improve cardiac function. And also reduced hypoxia-induced inflammation in cardiomyocytes and macrophages induced by IFN and LPS. It produced a similar protective effect in cardiomyocytes co-cultured with macrophages. Through microarray analysis, RNA-binding protein immunoprecipitation analysis, and other related experiments verification, TLR2 and TLR4 may be as potential targets of CCRR after MI. Our findings provide the evidence that lncRNA CCRR plays a key cardioprotective role against MI injury by targeting the TLR signaling pathway. nflammatory response plays a bidirectional regulatory role in myocardial infarction (MI). TLR signaling pathway plays an important role in the development of inflammation. Additionally, we discovered that CCRR is an anti-arrhythmic lncRNA in a prior work. Here we show, it is decreased in mice with 3-day MI followed by a sharp increase of pro-inflammatory cytokines and activation of the TLR pathway. Overexpression of CCRR could effectively inhibit the inflammatory response, reduce the infarct area, and improve cardiac function. And also reduced hypoxia-induced inflammation in cardiomyocytes and macrophages induced by IFN and LPS. It produced a similar protective effect in cardiomyocytes co-cultured with macrophages. Through microarray analysis, RNA-binding protein immunoprecipitation analysis, and other related experiments verification, TLR2 and TLR4 may be as potential targets of CCRR after MI. Our findings provide the evidence that lncRNA CCRR plays a key cardioprotective role against MI injury by targeting the TLR signaling pathway.

Project description:Coronary heart disease is the leading cause of death worldwide. After an acute myocardial infarction, early reperfusion reduces infarct size, which correlates with improved clinical outcomes. Paradoxically, reperfusion although relieving ischemia, accelerates apoptosis in injured cardiomyocytes, which has led to the view that myocardial salvage is futile beyond the first few hours of reperfusion. In murine hearts subjected to 90 min of coronary artery occlusion and then 48 h of reperfusion, we show transient activation of intrinsic prosurvival insulin-like growth factor-1 (IGF-1) signaling. In these hearts, acute IGF-1 receptor inhibition decreases the abundance of prosurvival signaling molecules, and markedly activates caspase-3, a potent effector of apoptosis, in infarct border zone cardiomyocytes. We found that mouse mast cell protease-4 (MMCP-4) degraded IGF-1 in vitro by a novel catalytic activity of chymases. In vivo, this degradation, which is triggered by mast cell infiltration into the peri-infarct region and MMCP-4 extravasation, between 48 and 72 h post-ischemia/reperfusion (I/R), attenuates IGF-1 prosurvival signaling. In MMCP-4-deficient mice, while infarct size is not reduced at 24 h post-I/R, at 72 h post-I/R myocardial IGF-1 levels and signaling are increased, resulting in activation of the survival kinases Akt and ERK, inhibition of caspase-3, and reduced myocardial cell death. As a consequence, I/R-mediated loss of viable myocardium, adverse cardiac remodeling and contractile impairment are markedly reduced. Cardiomyocyte survival with consequent myocardial salvage may thus be possible even days after an ischemic insult, making them a novel therapeutic target for delayed cardioprotective therapy. Group 1 is wild type C57Bl6 uninjured hearts. These mice were not undergone any surgery and used as controls. Group 2 are wild type C57Bl6 72 h post-ischemia reperfusion (IR) injury hearts. These mice for subjected to ischemia reperfusion (IR) involving 90 min of left anterior descending coronary artery occlusion followed by reperfusion for 3 days or 72 h.

Dataset Information

SPA-1 attenuate myocardial hypoxia and reoxygenation injury via regulating RAC1: an iTRAQ-based proteomic study

Publications

MicroRNA‑194‑5p attenuates hypoxia/reoxygenation‑induced apoptosis in H9C2 cardiomyocytes by inhibiting the over‑activation of RAC1 protein.

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