Dataset Information

Quantitative cardiac phosphoproteomics profiling during ischemic/reperfusion in an immature swine model

ABSTRACT: Ischemia/Reperfusion (I/R) results in altered metabolic and molecular responses. Phosphorylation, a posttranslational modification, is one of the most noted regulatory mechanisms and differential phosphorylation affects numerous regulatory and signaling mechanisms. To further understand the phosphoproteomic changes that occur in the heart during I/R we utilized iTRAQ-based quantitative proteomic and LC-MS/MS techniques to obtain a profile of phosphopeptides expressed under control and I/R conditions. A total of 1896 phosphopeptides were identified, and 116 were assessed as significant. The 116 phosphopeptides represented 87 unique proteins. Analysis of the phosphopeptides using Motif-x identified 2 predominant motifs: arginine and proline-directed serine phosphorylation sites. Two proteins known to be altered by I/R were among the dataset obtained, phospholamban and pyruvate dehydrogenase, and were used to confirm validity of the profile. Functional characterization of the phosphopetides identified in this study could lead to further understanding of the signaling mechanisms involved during I/R damage in the heart, as well as identifying new areas to target therapeutic strategies.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)

TISSUE(S): Cardiac Muscle, Cardiac Muscle Cell

DISEASE(S): Hypertrophic Cardiomyopathy

SUBMITTER: Matthew Monroe

LAB HEAD: Michael Portman, MD

PROVIDER: PXD006066 | Pride | 2017-05-02

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MP_Heart_iTRAQ_01_Phos2_12May14_Frodo_14-01-36.mgf	Mgf
	MP_Heart_iTRAQ_01_Phos2_12May14_Frodo_14-01-36.pride.mgf.gz	Mgf
	MP_Heart_iTRAQ_01_Phos2_12May14_Frodo_14-01-36.raw	Raw
	MP_Heart_iTRAQ_01_Phos2_12May14_Frodo_14-01-36_msgfplus.mzid.gz	Mzid
	MP_Heart_iTRAQ_01_Phos2_12May14_Frodo_14-01-36_msgfplus.pride.mztab.gz	Mztab

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Publications

Quantitative cardiac phosphoproteomics profiling during ischemia-reperfusion in an immature swine model.

Ledee Dolena D Kang Min A MA Kajimoto Masaki M Purvine Samuel S Brewer Heather H Pasa-Tolic Ljiljana L Portman Michael A MA

American journal of physiology. Heart and circulatory physiology 20170428 1

Ischemia-reperfusion (I/R) results in altered metabolic and molecular responses, and phosphorylation is one of the most noted regulatory mechanisms mediating signaling mechanisms during physiological stresses. To expand our knowledge of the potential phosphoproteomic changes in the myocardium during I/R, we used Isobaric Tags for Relative and Absolute Quantitation-based analyses in left ventricular samples obtained from porcine hearts under control or I/R conditions. The data are available via P ...[more]

PMID: 28455290

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Project description:Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value. Here, we report that the transcription factor Zinc finger E-box-binding homeobox2 (ZEB2) is induced by Hypoxia-inducible factor 1-alpha (HIF1a) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+-handling and contractility during ischemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed ZEB2 in cardiomyocytes to be necessary and sufficient to protect the heart against ischemia-induced diastolic dysfunction and structural remodeling. Moreover, RNA sequencing (RNA-seq) of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signaling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodeling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with antimiR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy. Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.