Dataset Information

Ischemic preconditioning predominantly affects phosphosites involved in myocardial contraction and promotes myocardial stunning while reducing infarction size in rats.

ABSTRACT: Background: Ischemic preconditioning (IPC), i.e., brief periods of ischemia, protect the heart from subsequent prolonged ischemic injury, and reduces infarction size. Myocardial stunning refers to transient loss of contractility in the heart after myocardial ischemia that recovers without causing permanent damage. The relationship between IPC and myocardial stunning remains incompletely understood. Purpose: The primary aim of this study was to examine the effects of IPC on the relationship between ischemia duration, stunning, and infarct size in an ischemia-reperfusion injury model. The secondary aim of the study was to examine to which extent the phosphoproteomic changes induced by IPC relate to myocardial contractile function. Methods: Rats were subjected to different durations of left anterior descending artery (LAD) occlusion, with or without preceding IPC. Echocardiograms were acquired at 4 and 48 hours to assess cardiac contraction in the affected myocardial segment. Reversible akinesia was defined as the presence of myocardial akinesia at 4 hours that resolved by 48 hours; and was considered to represent myocardial stunning. Infarction size was evaluated using triphenyl tetrazolium chloride staining. Phosphoproteomic analysis was performed in heart tissue from preconditioned and non-preconditioned animals using nano-liquid chromatography-mass spectrometry. Results: Reversible akinesia was observed in a majority of the rats that were subjected to IPC and subsequently exposed to ischemia of 13.5 or 15 minutes of ischemia (83.3% [n/N] and 66.6% [n/N] respectively). Among rats without IPC, who were exposed to either 10, 11, 12 or 13.5 minutes of ischemia, reversible akinesia was observed in 0% (n/N), 17% (2/12), 0% (n/N) and 0% (n/N) of rats (p<0.001). Phosphoproteomic analysis revealed significant differential regulation of 809 phosphopeptides between IPC and non-IPC groups, with significant associations with the sarcomere, Z-disc, and actin binding. Conclusion: Our study shows that IPC preferentially induces changes in phosphosites of proteins involved in myocardial contraction, and both increases the incidence of reversible post-ischemic myocardial stunning after ischemia-reperfusion injury and reduces infarction size.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

SUBMITTER: Evelin Berger

LAB HEAD: Carina Sihlbom Wallem

PROVIDER: PXD050441 | Pride | 2024-05-15

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	4435-4454-4513_Method_FASP_TMTpro_phospho_BpH_Lumos_230113EB.docx	Other
	4435-4513_R18-UPrat_Lumos220614_61-83Lumos221109_10-31_5procFDRproteins_proteome-control.xlsx	Xlsx
	4454-4513_R18-UPrat_TMTpro_phosSTY_stepped0to2mc_Lumos220706_05-18Lumos221109_36-48.pdResult	Other
	4454-4513_R18-UPrat_TMTpro_phosSTY_stepped0to2mc_Lumos220706_05-18Lumos221109_36-48_1procFDRphospeptides.xlsx	Xlsx
	4454-4513_R18-UPrat_TMTpro_phosSTY_stepped0to2mc_Lumos220706_05-18Lumos221109_36-48_5procFDRphosproteins.xlsx	Xlsx

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Publications

Ischemic preconditioning affects phosphosites and accentuates myocardial stunning while reducing infarction size in rats.

Elmahdy Ahmed A Shekka Espinosa Aaron A Kakaei Yalda Y Pylova Tetiana T Jha Abhishek A Zulfaj Ermir E Krasnikova Maryna M Al-Awar Amin A Sheybani Zahra Z Sevastianova Valentyna V Berger Evelin E Nejat Amirali A Molander Linnea L Andersson Erik Axel EA Omerovic Elmir E Hussain Shafaat S Redfors Björn B

Frontiers in cardiovascular medicine 20240315

<h4>Background and aims</h4>Ischemic preconditioning (IPC), i.e., brief periods of ischemia, protect the heart from subsequent prolonged ischemic injury, and reduces infarction size. Myocardial stunning refers to transient loss of contractility in the heart after myocardial ischemia that recovers without permanent damage. The relationship between IPC and myocardial stunning remains incompletely understood. This study aimed primarily to examine the effects of IPC on the relationship between ische ...[more]

PMID: 38559672

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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.