Mechanism of oleic acid-induced gap junctional disassembly in rat cardiomyocytes

Huang, Yuahn Sieh; Tseng, Yung Zu; Wu, Jyh‐Lin; Wang, Seu Mei

doi:10.1016/j.yjmcc.2004.06.011

Cited by 22 publications

(21 citation statements)

References 53 publications

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“…, 1993; Martinez & Saez, 1999) or activate signaling pathways such as protein kinase C leading to gap junction uncoupling (Lavado et al. , 1997; Huang et al. , 2004).…”

Section: Introductionsupporting

confidence: 87%

Docosahexaenoic acid (22:6n‐3) enrichment of membrane phospholipids increases gap junction coupling capacity in cultured astrocytes

Champeil‐Potokar¹,

Chaumontet²,

Guesnet³

et al. 2006

Eur J of Neuroscience

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Although it is agreed that n-3 polyunsaturated fatty acids (PUFAs) are important for brain function, it has yet to be demonstrated how they are involved in precise cellular mechanisms. We investigated the role of enhanced n-3 PUFA in astrocyte membranes on the gap junction capacity of these cells. Astrocytes isolated from newborn rat cortices were grown in medium supplemented with docosahexaenoic acid (DHA), the main n-3 PUFA in cell membranes, or arachidonic acid (AA), the main n-6 PUFA, plus an antioxidant (alpha-tocopherol or N-acetyl-cystein) to prevent peroxidation. The resulting three populations of astrocytes differed markedly in their n-3:n-6 PUFA ratios in phosphatidylethanolamine and phosphatidylcholine, the main phospholipids in membranes. DHA-supplemented cells had a physiological high n-3:n-6 ratio (1.58), unsupplemented cells had a low n-3:n-6 ratio (0.66) and AA-supplemented cells had a very low n-3:n-6 ratio (0.36), with excess n-6 PUFA. DHA-supplemented astrocytes had a greater gap junction capacity than unsupplemented cells or AA-supplemented cells. The enhanced gap junction coupling of DHA-enriched cells was associated with a more functional distribution of connexin 43 at cell interfaces (shown by immunocytochemistry) and more of the main phosphorylated isoform of connexin 43. These findings suggest that the high n-3:n-6 PUFA ratio that occurs naturally in astrocyte membranes is needed for optimal gap junction coupling in these cells.

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“…, 1993; Martinez & Saez, 1999) or activate signaling pathways such as protein kinase C leading to gap junction uncoupling (Lavado et al. , 1997; Huang et al. , 2004).…”

Section: Introductionsupporting

confidence: 87%

Docosahexaenoic acid (22:6n‐3) enrichment of membrane phospholipids increases gap junction coupling capacity in cultured astrocytes

Champeil‐Potokar¹,

Chaumontet²,

Guesnet³

et al. 2006

Eur J of Neuroscience

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“…Erk was reported to be critical for cardiac Cx43 upregulation and increased GJIC [43]. However, PKC-induced Cx43 Ser368 phosphorylation resulted in disassembly of the gap junction and reduced channel conductance [39,44], indicating the negative effect of GJIC by PKC activation. It might partly explain the unchanged GJIC function by AGE treatment in spite of Cx43 upregulation.…”

Section: Resultsmentioning

confidence: 99%

Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in Rat Cardiomyocytes via PKC and Erk MAPK Pathways

Lu¹,

Zhao²,

Xu³

et al. 2013

IJMS

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The remodeling of cardiac gap junction contributes to the arrhythmias in a diabetic heart. We previously reported that high glucose reduced Cx43 protein level in neonatal rat cardiomyocytes. But, the effect and mechanisms of advanced glycation end product (AGE) on Cx43 expression still remain unclear. In this study, we measured the AGE receptor (RAGE) and Cx43 expression by immunohistochemisty in AGE-infused Sprague-Dawley (SD) rats. In vitro, the Cx43 and RAGE levels were detected in AGE-treated cardiomyocytes by Western blot and real-time RT-PCR. The function of cells coupling was measured by Scrap loading dye transfer assay. Our results showed that the AGE-infused rat hearts exhibited increased cardiac RAGE and Cx43, as well as Cx43 redistribution. In cultured cardiomyocytes, AGE elevated RAGE expression in a time- and dose-dependent manner. Cx43 protein and mRNA levels were upregulated by AGE (200 mg/L, 24 h), but the gap junction function was not enhanced. RAGE-targeted knock-down or the addition of PKC, and Erk inhibitors abolished the effect of AGE on Cx43. Therefore, AGE-RAGE system might elevate Cx43 expression in rat cardiomyocytes by activating PKC and Erk MAPK pathways, and it also enhanced Cx43 redistribution in vivo, which might contribute to the arrhythmias in diabetes.

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“…Cells were allowed to adhere to the plates for at least 24 h before different treatments. Cells were cultured in maintenance medium (4.5:1 DMEM: M199, 2% FBS, 1% penicillin/streptomycin/fungizone) supplemented with normal glucose (5.5 mM plus 25 mM mannitol), normal glucose (5.5 mM plus 25 mM mannitol) plus oleic acid (400 M), high glucose (30 mM), or high glucose plus oleic acid (400 M) (16,17), referred to as control and oleic acid, respectively. The culture medium was changed daily for 3 days until the cells were harvested.…”

Section: Methodsmentioning

confidence: 99%

Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy

Fricovsky

Suárez

Ihm

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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We examined the role that enzymatic protein O-GlcNAcylation plays in the development of diabetic cardiomyopathy in a mouse model of Type 2 diabetes mellitus (DM2). Mice injected with low-dose streptozotocin and fed a high-fat diet developed mild hyperglycemia and obesity consistent with DM2. Studies were performed from 1 to 6 mo after initiating the DM2 protocol. After 1 mo, DM2 mice showed increased body weight, impaired fasting blood glucose, and hyperinsulinemia. Echocardiographic evaluation revealed left ventricular diastolic dysfunction by 2 mo and O-GlcNAcylation of several cardiac proteins and of nuclear transcription factor Sp1. By 4 mo, systolic dysfunction was observed and sarcoplasmic reticulum Ca(2+) ATPase expression decreased by 50%. Fibrosis was not observed at any timepoint in DM2 mice. Levels of the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine:fructose-6-phosphate amidotransferase (GFAT) were increased as early as 2 mo. Fatty acids, which are elevated in DM2 mice, can possibly be linked to excessive protein O-GlcNAcylation levels, as cultured cardiac myocytes in normal glucose treated with oleic acid showed increased O-GlcNAcylation and GFAT levels. These data indicate that the early onset of diastolic dysfunction followed by the loss of systolic function, in the absence of cardiac hypertrophy or fibrosis, is associated with increased cardiac protein O-GlcNAcylation and increased O-GlcNAcylation levels of key calcium-handling proteins. A link between excessive protein O-GlcNAcylation and cardiac dysfunction is further supported by results showing that reducing O-GlcNAcylation by O-GlcNAcase overexpression improved cardiac function in the diabetic mouse. In addition, fatty acids play a role in stimulating excess O-GlcNAcylation. The nature and time course of changes observed in cardiac function suggest that protein O-GlcNAcylation plays a mechanistic role in the triggering of diabetic cardiomyopathy in DM2.

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Mechanism of oleic acid-induced gap junctional disassembly in rat cardiomyocytes

Cited by 22 publications

References 53 publications

Docosahexaenoic acid (22:6n‐3) enrichment of membrane phospholipids increases gap junction coupling capacity in cultured astrocytes

Docosahexaenoic acid (22:6n‐3) enrichment of membrane phospholipids increases gap junction coupling capacity in cultured astrocytes

Advanced Glycation End Product (AGE)-AGE Receptor (RAGE) System Upregulated Connexin43 Expression in Rat Cardiomyocytes via PKC and Erk MAPK Pathways

Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy

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