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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

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.


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ET-1-induced phosphorylation of ERK1/2 was blocked by PD98059.
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Figure 3: ET-1-induced phosphorylation of ERK1/2 was blocked by PD98059.

Mentions: To further investigate the role of ERK1/2 signaling in ET-1-induced cardiomyocyte hypertrophy, the cells were pre-treated with the specific ERK1/2 phosphorylation inhibitor PD98059. As expected, treatment with PD98059 completely prevented the ET-1-induced ERK1/2 phosphorylation in CMs from both SHR and WKY rats as analyzed with Western blot (Fig. 3). PD98059 treatment had no effect on the cell surface area in the control cells (no exposure to ET-1) (Fig. 2B). However, pre-treatment with PD98059 totally blocked the ET-1-induced increase in cell surface area in CMs from both SHR and WKY rats (Fig. 2B). The surface area of the cells treated with ET-1 in the presence of PD98059 was the same as that of control cells. Similarly, when the cells were pre-treated with PD98059, the ET-1-induced increase in [3H]-leucine incorporation was completely reversed in CMs from both SHR and WKY rats (Fig. 4). Of note, treatment with PD98059 had no impact on the basal [3H]-leucine incorporation in CMs from either SHR or WKY rats. These results further suggested that ET-1-induced hypertrophy was mediated through ERK1/2 signaling 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
ET-1-induced phosphorylation of ERK1/2 was blocked by PD98059.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: ET-1-induced phosphorylation of ERK1/2 was blocked by PD98059.
Mentions: To further investigate the role of ERK1/2 signaling in ET-1-induced cardiomyocyte hypertrophy, the cells were pre-treated with the specific ERK1/2 phosphorylation inhibitor PD98059. As expected, treatment with PD98059 completely prevented the ET-1-induced ERK1/2 phosphorylation in CMs from both SHR and WKY rats as analyzed with Western blot (Fig. 3). PD98059 treatment had no effect on the cell surface area in the control cells (no exposure to ET-1) (Fig. 2B). However, pre-treatment with PD98059 totally blocked the ET-1-induced increase in cell surface area in CMs from both SHR and WKY rats (Fig. 2B). The surface area of the cells treated with ET-1 in the presence of PD98059 was the same as that of control cells. Similarly, when the cells were pre-treated with PD98059, the ET-1-induced increase in [3H]-leucine incorporation was completely reversed in CMs from both SHR and WKY rats (Fig. 4). Of note, treatment with PD98059 had no impact on the basal [3H]-leucine incorporation in CMs from either SHR or WKY rats. These results further suggested that ET-1-induced hypertrophy was mediated through ERK1/2 signaling 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.


Related in: MedlinePlus