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Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension

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ABSTRACT

Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.

No MeSH data available.


Inhibition of PI3 kinase / Akt signaling prevented ET-1-induced ERK1/2 phosphorylation and protein synthesis in CMs from SHR and WKY rats.
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Figure 6: Inhibition of PI3 kinase / Akt signaling prevented ET-1-induced ERK1/2 phosphorylation and protein synthesis in CMs from SHR and WKY rats.

Mentions: ET-1-induced Akt activation occurred after 3 hrs of stimulation, and slowly declined afterwards. The pattern of ET-1-induced Akt activation was similar in the cells from both SHR and WKY rats. When the cells were pre-treated with LY294002, the baseline Akt phosphorylation was not affected. However, the ET-1-induced increase in Akt phosphorylation was completely reversed to the baseline level (Fig. 6A). Interestingly, pre-treatment of CMs with LY294002 also completely prevented ET-1-induced ERK1/2 phosphorylation in both SHR and WKY rats (Fig. 6B), suggesting that PI3 kinase / Akt signaling is crucial to ET-1-induced ERK1/2 activation in these cells. In parallel to ERK1/2 activation, pre-treatment of CMs with LY294002 also inhibited ET-1-induced protein synthesis as evaluated with [3H]-leucine incorporation assay (Fig. 6c. These data indicate that PI3 kinase / Akt /ERK1/2 signaling plays an important role in ET-1-induced hypertrophy of CMs in both SHR and WKY rats.


Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension
Inhibition of PI3 kinase / Akt signaling prevented ET-1-induced ERK1/2 phosphorylation and protein synthesis in CMs from SHR and WKY rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997939&req=5

Figure 6: Inhibition of PI3 kinase / Akt signaling prevented ET-1-induced ERK1/2 phosphorylation and protein synthesis in CMs from SHR and WKY rats.
Mentions: ET-1-induced Akt activation occurred after 3 hrs of stimulation, and slowly declined afterwards. The pattern of ET-1-induced Akt activation was similar in the cells from both SHR and WKY rats. When the cells were pre-treated with LY294002, the baseline Akt phosphorylation was not affected. However, the ET-1-induced increase in Akt phosphorylation was completely reversed to the baseline level (Fig. 6A). Interestingly, pre-treatment of CMs with LY294002 also completely prevented ET-1-induced ERK1/2 phosphorylation in both SHR and WKY rats (Fig. 6B), suggesting that PI3 kinase / Akt signaling is crucial to ET-1-induced ERK1/2 activation in these cells. In parallel to ERK1/2 activation, pre-treatment of CMs with LY294002 also inhibited ET-1-induced protein synthesis as evaluated with [3H]-leucine incorporation assay (Fig. 6c. These data indicate that PI3 kinase / Akt /ERK1/2 signaling plays an important role in ET-1-induced hypertrophy of CMs in both SHR and WKY rats.

View Article: PubMed Central - PubMed

ABSTRACT

Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.

No MeSH data available.