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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.


Related in: MedlinePlus

The specific ERK1/2 kinase inhibitor PD98059 suppressed ET-1-induced protein synthesis in CMs. Enhanced protein synthesis by ET-1 was observed in CMs in SHR and WKY rats, especially in the cells from SHR. Pre-treatment of the cells with PD98059 completely blocked ET-1-induced protein synthesis as evaluated with [3H]-leucine incorporation assay. Data were presented as means ± SEM of three different experiments (each in triplicate).
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Figure 4: The specific ERK1/2 kinase inhibitor PD98059 suppressed ET-1-induced protein synthesis in CMs. Enhanced protein synthesis by ET-1 was observed in CMs in SHR and WKY rats, especially in the cells from SHR. Pre-treatment of the cells with PD98059 completely blocked ET-1-induced protein synthesis as evaluated with [3H]-leucine incorporation assay. Data were presented as means ± SEM of three different experiments (each in triplicate).

Mentions: As expected, when CMs were exposed to ET-1, the cells exhibited a symmetric growth with a significant increase in cell surface area (Fig. 2A & B). The cell surface area was increased by 40% and 30% for CMs from SHR and WKY rats, respectively, after ET-1 treatment (n=3, p < 0.01). The ET-1-induced increase in cell surface area was accompanied by an enhanced density of intracellular actin in the cells as evaluated by fluorescent phalloidin staining (Fig. 2C). The hypertrophic response to ET-1 was supported by increased protein synthesis as evaluated using [3H]-leucine incorporation assay. There was a low level of basal protein synthesis in the cells from both SHR and WKY rats without ET-1 stimulation that was significantly increased by 80% and 62% for CMs from SHR and WKY rats (p < 0.05, n=3, Fig. 4), respectively. These data demonstrated that ET-1 induced a greater hypertrophic response with increased cell surface area and protein synthesis in CMs from SHR than that in the cells from 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
The specific ERK1/2 kinase inhibitor PD98059 suppressed ET-1-induced protein synthesis in CMs. Enhanced protein synthesis by ET-1 was observed in CMs in SHR and WKY rats, especially in the cells from SHR. Pre-treatment of the cells with PD98059 completely blocked ET-1-induced protein synthesis as evaluated with [3H]-leucine incorporation assay. Data were presented as means ± SEM of three different experiments (each in triplicate).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: The specific ERK1/2 kinase inhibitor PD98059 suppressed ET-1-induced protein synthesis in CMs. Enhanced protein synthesis by ET-1 was observed in CMs in SHR and WKY rats, especially in the cells from SHR. Pre-treatment of the cells with PD98059 completely blocked ET-1-induced protein synthesis as evaluated with [3H]-leucine incorporation assay. Data were presented as means ± SEM of three different experiments (each in triplicate).
Mentions: As expected, when CMs were exposed to ET-1, the cells exhibited a symmetric growth with a significant increase in cell surface area (Fig. 2A & B). The cell surface area was increased by 40% and 30% for CMs from SHR and WKY rats, respectively, after ET-1 treatment (n=3, p < 0.01). The ET-1-induced increase in cell surface area was accompanied by an enhanced density of intracellular actin in the cells as evaluated by fluorescent phalloidin staining (Fig. 2C). The hypertrophic response to ET-1 was supported by increased protein synthesis as evaluated using [3H]-leucine incorporation assay. There was a low level of basal protein synthesis in the cells from both SHR and WKY rats without ET-1 stimulation that was significantly increased by 80% and 62% for CMs from SHR and WKY rats (p < 0.05, n=3, Fig. 4), respectively. These data demonstrated that ET-1 induced a greater hypertrophic response with increased cell surface area and protein synthesis in CMs from SHR than that in the cells from WKY rats.

View Article: PubMed Central - PubMed

ABSTRACT

Extracellular signal regulated kinase&frac12; (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