Effects of Hyperglycemia on Vascular Smooth Muscle Ca2+ Signaling.

Nahed El-Najjar,Khaled Machaca,Rawad Hodeify,Rashmi P Kulkarni,Nancy Nader

doi:10.1155/2017/3691349

Nahed El-Najjar, Khaled Machaca + Show 3 more

Open Access

https://doi.org/10.1155/2017/3691349

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Abstract

Diabetes is a complex disease that is characterized with hyperglycemia, dyslipidemia, and insulin resistance. These pathologies are associated with significant cardiovascular implications that affect both the macro- and microvasculature. It is therefore important to understand the effects of various pathologies associated with diabetes on the vasculature. Here we directly test the effects of hyperglycemia on vascular smooth muscle (VSM) Ca2+ signaling in an isolated in vitro system using the A7r5 rat aortic cell line as a model. We find that prolonged exposure of A7r5 cells to hyperglycemia (weeks) is associated with changes to Ca2+ signaling, including most prominently an inhibition of the passive ER Ca2+ leak and the sarcoplasmic reticulum Ca2+-ATPase (SERCA). To translate these findings to the in vivo condition, we used primary VSM cells from normal and diabetic subjects and find that only the inhibition of the ER Ca2+ leaks replicates in cells from diabetic donors. These results show that prolonged hyperglycemia in isolation alters the Ca2+ signaling machinery in VSM cells. However, these alterations are not readily translatable to the whole organism situation where alterations to the Ca2+ signaling machinery are different.

Highlights

Diabetes is a complex multifactorial disease characterized by the onset of dyslipidemia, early hyperinsulinemia, and hyperinsulinemia, followed by pancreatic β-cell failure leading to hyperglycemia and insulin resistance [1,2,3]
Based on these findings our goal from the present work was to investigate the effect of prolonged exposure to high glucose levels on Ca2+ homeostasis in the A7r5 vascular smooth muscle (VSM) cell line to better understand the potential pathology of hyperglycemia on the Ca2+ signaling machinery of VSM and potential implications on cardiovascular disease
To test whether cells cultured under high glucose (HG) have higher reactive oxygen species (ROS) level than those cultured in normal glucose (NG) and osmotic control (OC) media, the level of ROS in cells cultured in media with different glucose concentration was examined using 2󸀠,7󸀠dichlorodihydrofluorescein diacetate (DCFH-DA) (Acros Organics, New Jersey, USA)

Summary

Introduction

Diabetes is a complex multifactorial disease characterized by the onset of dyslipidemia, early hyperinsulinemia, and hyperinsulinemia, followed by pancreatic β-cell failure leading to hyperglycemia and insulin resistance [1,2,3]. Searls et al showed that in contrast to the defects observed in diabetic mice Ca2+ signaling pathways in A7r5 cells were not affected when the cells were shifted for short term from the physiological 5 mM glucose to the glycemic 25 mM and supraphysiological glucose 75 mM concentration was needed to see a significant effect [34] Based on these findings our goal from the present work was to investigate the effect of prolonged exposure to high glucose levels on Ca2+ homeostasis in the A7r5 VSM cell line to better understand the potential pathology of hyperglycemia on the Ca2+ signaling machinery of VSM and potential implications on cardiovascular disease

Materials and Methods

Results

PE 5 휇M

Discussion

Disclosure