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By Chowdhury S. Abdullah, Shafiul Alam, Richa Aishwarya, Jonette M. Green, A. Wayne Orr, Matthew D. Woolard, Aimee E. Vozelinek, Norman R. Harris, Randa S. Eshaq, Christopher G. Kevil, and Shenuarin Bhuiyan

Introduction to the article published in Journal of Molecular and Cellular Cardiology, 046| VOLUME 112, P149, NOVEMBER 01, 2017, DOI: https://doi.org/10.1016/j.yjmcc.2017.07.058

Editor’s Highlights

• Sigma-1 receptor (Sigmar1) agonist exerts a protective function of Sigmar1 in cardiac dysfunction induced by obesity metabolic-stress.

Abstract

Rationale: Cellular energy metabolism and integrity are maintained by mitochondria. Mitochondrial dysfunction plays a crucial role in the pathogenesis of metabolic disorders. Sigma-1 receptor (Sigmar1) is a highly expressed molecular chaperone protein in the heart but its molecular function in metabolic disorders-induced cardiac remodeling remains unknown. Objective: We aim to investigate Sigmar1’s molecular function in metabolic stress-induced cardiac remodeling. Methods and Results: We found the Sigmar1 localization in the mitochondrial and mitochondrial-associated ER membrane fraction by subcellular fractionation and biochemical experiments. To define the role of Sigmar1 in metabolic disorder, we maintained C57BL/6J male mice on standard rodent diet (control) and high fat diet (HFD) (60% calorie from fat) for 6 months. HFD-fed mice showed marked myocardial dysfunction represented by decreased percent fraction shortening and percent ejection fraction measured by echocardiogram. Sigmar1 expression was significantly increased in HFD-fed mice heart compared to control mice. Similarly, we also found increased Sigmar1 expression in the heart of db/db mice, a genetic mouse model of obesity. Intriguingly, streptozotocin-treated hyperglycemic rodents did not exhibit any changes in Sigmar1 expression in heart compared to saline treated group. To further define the molecular function of Sigmar1 in these mice, we maintained the Sigmar1 knockout mice and control mice on HFD for the same duration. Sigmar1 knockout mice showed deteriorated cardiac function and adverse cardiac remodeling indicating a protective role of Sigmar1. Conclusions: Our findings suggested a potential protective function of Sigmar1 in metabolic-stress induced cardiac dysfunction and adverse remodeling.