Dysregulation of the calcium handling protein, CCDC47, is associated with diabetic cardiomyopathy

Khampaseuth Thapa,Rangaprasad Sarangarajan,Stephane Gesta,Armando J Mendez,Angela Szeto,Vivek K Vishnudas,Niven R Narain,Aishwarya Sarma,Kai Connie Wu,Eric M Grund

doi:10.1186/s13578-018-0244-0

Khampaseuth Thapa, Rangaprasad Sarangarajan + Show 8 more

Open Access

https://doi.org/10.1186/s13578-018-0244-0

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Journal: Cell & Bioscience	Publication Date: Aug 17, 2018
Citations: 7	License type: open-access

Affiliation: University of Miami

Abstract

BackgroundDiabetes mellitus is associated with an increased risk in diabetic cardiomyopathy (DCM) that is distinctly not attributed to co-morbidities with other vasculature diseases. To date, while dysregulation of calcium handling is a key hallmark in cardiomyopathy, studies have been inconsistent in the types of alterations involved. In this study human cardiomyocytes were exposed to an environmental nutritional perturbation of high glucose, fatty acids, and l-carnitine to model DCM and iTRAQ-coupled LC–MS/MS proteomic analysis was used to capture proteins affected by the perturbation. The proteins captured were then compared to proteins currently annotated in the cardiovascular disease (CVD) gene ontology (GO) database to identify proteins not previously described as being related to CVD. Subsequently, GO analysis for calcium regulating proteins and endoplasmic/sarcoplasmic reticulum (ER/SR) associated proteins was carried out.ResultsHere, we identified CCDC47 (calumin) as a unique calcium regulating protein altered in our in vitro nutritional perturbation model. The cellular and functional role of CCDC47 was then assessed in rat cardiomyocytes. In rat H9C2 myocytes, overexpression of CCDC47 resulted in increase in ionomycin-induced calcium release and reuptake. Of interest, in a diet-induced obese (DIO) rat model of DCM, CCDC47 mRNA expression was increased in the atrium and ventricle of the heart, but CCDC47 protein expression was significantly increased only in the atrium of DIO rats compared to lean control rats. Notably, no changes in ANP, BNP, or β-MHC were observed between DIO rats and lean control rats.ConclusionsTogether, our in vitro and in vivo studies demonstrate that CCDC47 is a unique calcium regulating protein that is associated with early onset hypertrophic cardiomyopathy.

Highlights

Diabetes mellitus is associated with an increased risk in diabetic cardiomyopathy (DCM) that is distinctly not attributed to co-morbidities with other vasculature diseases
Identification of unique proteins associated with calcium regulation in an in vitro nutritional model of cardiomyopathy DCM is associated with increased circulating free fatty acids, hyperglycemia and inflammation, which contributes to endoplasmic reticulum (ER) stress, shift in cellular metabolism, disruption of intracellular signaling and calcium handling [3]
To confirm that the likelihood of proteins captured in the cardiovascular disease (CVD) database are higher than being captured in a non-CVD database the 912 differential proteins were compared to the UniProt-GOA renal disease database

Summary

Introduction

Diabetes mellitus is associated with an increased risk in diabetic cardiomyopathy (DCM) that is distinctly not attributed to co-morbidities with other vasculature diseases. Diabetes mellitus is associated with an increased risk in diabetic cardiomyopathy (DCM) that is distinctly not attributed to co-morbidities with other vasculature diseases, which include coronary artery disease (CAD) or hypertension [1, 2]. It is characterized by early-onset diastolic dysfunction followed by late-onset systolic dysfunction, which is thought to be mediated by cardiac remodeling and hypertrophy [3]. Of particular interest, is that dysregulation of calcium (Ca2+) handling has been reported as playing a key role in development of DCM [2, 3, 5]

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