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Trichostatin A Modulates Angiotensin II-induced Vasoconstriction and Blood Pressure Via Inhibition of p66shc Activation.

Kang G, Lee YR, Joo HK, Park MS, Kim CS, Choi S, Jeon BH - Korean J. Physiol. Pharmacol. (2015)

Bottom Line: The vasoconstriction induced by angiotensin II (Ang II, 100 nM) was inhibited by TSA in both endothelium-intact and endothelium-denuded rat aortas, suggesting that TSA has mainly acted in vascular smooth muscle cells (VSMCs).In cultured rat aortic VSMCs, Ang II increased p66shc phosphorylation, which was inhibited by the Ang II receptor type I (AT1R) inhibitor, valsartan (10 µM), but not by the AT2R inhibitor, PD123319.TSA (1~10 µM) inhibited Ang II-induced p66shc phosphorylation in VSMCs and in HEK293T cells expressing AT1R.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Medical Sciences, Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Korea.

ABSTRACT
Histone deacetylase (HDAC) has been recognized as a potentially useful therapeutic target for cardiovascular disorders. However, the effect of the HDAC inhibitor, trichostatin A (TSA), on vasoreactivity and hypertension remains unknown. We performed aortic coarctation at the inter-renal level in rats in order to create a hypertensive rat model. Hypertension induced by abdominal aortic coarctation was significantly suppressed by chronic treatment with TSA (0.5 mg/kg/day for 7 days). Nicotinamide adenine dinucleotide phosphate-driven reactive oxygen species production was also reduced in the aortas of TSA-treated aortic coarctation rats. The vasoconstriction induced by angiotensin II (Ang II, 100 nM) was inhibited by TSA in both endothelium-intact and endothelium-denuded rat aortas, suggesting that TSA has mainly acted in vascular smooth muscle cells (VSMCs). In cultured rat aortic VSMCs, Ang II increased p66shc phosphorylation, which was inhibited by the Ang II receptor type I (AT1R) inhibitor, valsartan (10 µM), but not by the AT2R inhibitor, PD123319. TSA (1~10 µM) inhibited Ang II-induced p66shc phosphorylation in VSMCs and in HEK293T cells expressing AT1R. Taken together, these results suggest that TSA treatment inhibited vasoconstriction and hypertension via inhibition of Ang II-induced phosphorylation of p66shc through AT1R.

No MeSH data available.


Related in: MedlinePlus

Angiotensin II evoked p66shc phosphorylation in vascular smooth muscle cells. Cells were treated first with DMSO (control) or the indicated concentrations of valsartan (angiotensin II receptor type 1 inhibitor) (A), or PD123319 (angiotensin II receptor type 2 inhibitor) (B) for 30 min, and subsequently with 100 nM Ang II. Cell lysates were immunoblotted for phospho-p66shc, Shc, and actin. Densitometric scanning was performed to quantify the phosphop66shc/p66shc levels. Bars represent the mean±S.E.M. (n=4). **p<0.01 (vs. control), #p<0.01 (vs. only angiotensin II-treated cells).
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Figure 3: Angiotensin II evoked p66shc phosphorylation in vascular smooth muscle cells. Cells were treated first with DMSO (control) or the indicated concentrations of valsartan (angiotensin II receptor type 1 inhibitor) (A), or PD123319 (angiotensin II receptor type 2 inhibitor) (B) for 30 min, and subsequently with 100 nM Ang II. Cell lysates were immunoblotted for phospho-p66shc, Shc, and actin. Densitometric scanning was performed to quantify the phosphop66shc/p66shc levels. Bars represent the mean±S.E.M. (n=4). **p<0.01 (vs. control), #p<0.01 (vs. only angiotensin II-treated cells).

Mentions: Activation of p66shc modulates the oxidative stress response and cellular survival. Circumstantial evidence suggests that activation of p66shc, which acts downstream of tyrosine kinase receptors, may be implicated in Ang II-induced cardiovascular alterations [16]. We therefore attempted to ascertain the Ang II receptor subtype is involved in p66shc activation in isolated rat VSMCs. As shown in Fig. 3, Ang II (100 nM) treatment led to increased phosphorylation of p66shc on serine 36, which was inhibited by the AT1R inhibitor, valsartan, but not by the AT2R inhibitor, PD123319. These data suggest that Ang II increases p66shc activation via AT1R in VSMCs.


Trichostatin A Modulates Angiotensin II-induced Vasoconstriction and Blood Pressure Via Inhibition of p66shc Activation.

Kang G, Lee YR, Joo HK, Park MS, Kim CS, Choi S, Jeon BH - Korean J. Physiol. Pharmacol. (2015)

Angiotensin II evoked p66shc phosphorylation in vascular smooth muscle cells. Cells were treated first with DMSO (control) or the indicated concentrations of valsartan (angiotensin II receptor type 1 inhibitor) (A), or PD123319 (angiotensin II receptor type 2 inhibitor) (B) for 30 min, and subsequently with 100 nM Ang II. Cell lysates were immunoblotted for phospho-p66shc, Shc, and actin. Densitometric scanning was performed to quantify the phosphop66shc/p66shc levels. Bars represent the mean±S.E.M. (n=4). **p<0.01 (vs. control), #p<0.01 (vs. only angiotensin II-treated cells).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553407&req=5

Figure 3: Angiotensin II evoked p66shc phosphorylation in vascular smooth muscle cells. Cells were treated first with DMSO (control) or the indicated concentrations of valsartan (angiotensin II receptor type 1 inhibitor) (A), or PD123319 (angiotensin II receptor type 2 inhibitor) (B) for 30 min, and subsequently with 100 nM Ang II. Cell lysates were immunoblotted for phospho-p66shc, Shc, and actin. Densitometric scanning was performed to quantify the phosphop66shc/p66shc levels. Bars represent the mean±S.E.M. (n=4). **p<0.01 (vs. control), #p<0.01 (vs. only angiotensin II-treated cells).
Mentions: Activation of p66shc modulates the oxidative stress response and cellular survival. Circumstantial evidence suggests that activation of p66shc, which acts downstream of tyrosine kinase receptors, may be implicated in Ang II-induced cardiovascular alterations [16]. We therefore attempted to ascertain the Ang II receptor subtype is involved in p66shc activation in isolated rat VSMCs. As shown in Fig. 3, Ang II (100 nM) treatment led to increased phosphorylation of p66shc on serine 36, which was inhibited by the AT1R inhibitor, valsartan, but not by the AT2R inhibitor, PD123319. These data suggest that Ang II increases p66shc activation via AT1R in VSMCs.

Bottom Line: The vasoconstriction induced by angiotensin II (Ang II, 100 nM) was inhibited by TSA in both endothelium-intact and endothelium-denuded rat aortas, suggesting that TSA has mainly acted in vascular smooth muscle cells (VSMCs).In cultured rat aortic VSMCs, Ang II increased p66shc phosphorylation, which was inhibited by the Ang II receptor type I (AT1R) inhibitor, valsartan (10 µM), but not by the AT2R inhibitor, PD123319.TSA (1~10 µM) inhibited Ang II-induced p66shc phosphorylation in VSMCs and in HEK293T cells expressing AT1R.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Medical Sciences, Department of Physiology, School of Medicine, Chungnam National University, Daejeon 301-747, Korea.

ABSTRACT
Histone deacetylase (HDAC) has been recognized as a potentially useful therapeutic target for cardiovascular disorders. However, the effect of the HDAC inhibitor, trichostatin A (TSA), on vasoreactivity and hypertension remains unknown. We performed aortic coarctation at the inter-renal level in rats in order to create a hypertensive rat model. Hypertension induced by abdominal aortic coarctation was significantly suppressed by chronic treatment with TSA (0.5 mg/kg/day for 7 days). Nicotinamide adenine dinucleotide phosphate-driven reactive oxygen species production was also reduced in the aortas of TSA-treated aortic coarctation rats. The vasoconstriction induced by angiotensin II (Ang II, 100 nM) was inhibited by TSA in both endothelium-intact and endothelium-denuded rat aortas, suggesting that TSA has mainly acted in vascular smooth muscle cells (VSMCs). In cultured rat aortic VSMCs, Ang II increased p66shc phosphorylation, which was inhibited by the Ang II receptor type I (AT1R) inhibitor, valsartan (10 µM), but not by the AT2R inhibitor, PD123319. TSA (1~10 µM) inhibited Ang II-induced p66shc phosphorylation in VSMCs and in HEK293T cells expressing AT1R. Taken together, these results suggest that TSA treatment inhibited vasoconstriction and hypertension via inhibition of Ang II-induced phosphorylation of p66shc through AT1R.

No MeSH data available.


Related in: MedlinePlus