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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

Chronic treatment of trichostatin A (TSA) inhibited aortic coarctation-induced hypertension. (A) Effect of chronic TSA treatment on blood pressure in sham-operated and aortic coarctation rats. Animals were treated for 7 days by subcutaneously administration of vehicle (DMSO) or TSA (0.5 mg/kg/day). Bars represent the mean±S.E.M. (n=4 or 5) for systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP). (B) Superoxide production in aortas of the abdominal aortic coarctation and sham-operated rats was determined by a lucigenin chemiluminescence assay. Bars represent the mean±S.E.M. (n=5 or 6). Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-driven superoxide were measured in the aortas of the rats. NADPH (0.1 mM) was added to measure NADPH oxidase activity. Sham, sham-operated group; AC, aortic coarctation; TSA, TSA-treated sham-operated group; AC+TSA, TSA-treated aortic coarctation group. *p<0.05 (vs. sham group). #p<0.05 (vs. aortic coarctation group).
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Figure 1: Chronic treatment of trichostatin A (TSA) inhibited aortic coarctation-induced hypertension. (A) Effect of chronic TSA treatment on blood pressure in sham-operated and aortic coarctation rats. Animals were treated for 7 days by subcutaneously administration of vehicle (DMSO) or TSA (0.5 mg/kg/day). Bars represent the mean±S.E.M. (n=4 or 5) for systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP). (B) Superoxide production in aortas of the abdominal aortic coarctation and sham-operated rats was determined by a lucigenin chemiluminescence assay. Bars represent the mean±S.E.M. (n=5 or 6). Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-driven superoxide were measured in the aortas of the rats. NADPH (0.1 mM) was added to measure NADPH oxidase activity. Sham, sham-operated group; AC, aortic coarctation; TSA, TSA-treated sham-operated group; AC+TSA, TSA-treated aortic coarctation group. *p<0.05 (vs. sham group). #p<0.05 (vs. aortic coarctation group).

Mentions: We investigated the effect of TSA on blood pressure in sham and aortic coarctation-induced hypertensive rats. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) were significantly higher in aortic coarctation-induced hypertensive rats. Chronic treatment with TSA (0.5 mg/kg/day) for 7 days significantly reduced high arterial blood pressure induced by aortic coarctation (Fig. 1A). As shown in Fig. 1A, chronic treatment with TSA significantly reduced SBP in aortic coarctation rats (169.8±8.2 mmHg vs. 133.1±3.5 mmHg, p<0.05), but did not reduce SBP in sham rats (125.5±3.0 mmHg vs. 112.9±9.5 mmHg). Additionally, even though DBP and MAP were reduced in TSA-treated sham and aortic coarctation-rats, the anti-hypertensive effect of TSA in aortic coarctation rats was greater than that in sham-operated rats.


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)

Chronic treatment of trichostatin A (TSA) inhibited aortic coarctation-induced hypertension. (A) Effect of chronic TSA treatment on blood pressure in sham-operated and aortic coarctation rats. Animals were treated for 7 days by subcutaneously administration of vehicle (DMSO) or TSA (0.5 mg/kg/day). Bars represent the mean±S.E.M. (n=4 or 5) for systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP). (B) Superoxide production in aortas of the abdominal aortic coarctation and sham-operated rats was determined by a lucigenin chemiluminescence assay. Bars represent the mean±S.E.M. (n=5 or 6). Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-driven superoxide were measured in the aortas of the rats. NADPH (0.1 mM) was added to measure NADPH oxidase activity. Sham, sham-operated group; AC, aortic coarctation; TSA, TSA-treated sham-operated group; AC+TSA, TSA-treated aortic coarctation group. *p<0.05 (vs. sham group). #p<0.05 (vs. aortic coarctation group).
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Related In: Results  -  Collection

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Figure 1: Chronic treatment of trichostatin A (TSA) inhibited aortic coarctation-induced hypertension. (A) Effect of chronic TSA treatment on blood pressure in sham-operated and aortic coarctation rats. Animals were treated for 7 days by subcutaneously administration of vehicle (DMSO) or TSA (0.5 mg/kg/day). Bars represent the mean±S.E.M. (n=4 or 5) for systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP). (B) Superoxide production in aortas of the abdominal aortic coarctation and sham-operated rats was determined by a lucigenin chemiluminescence assay. Bars represent the mean±S.E.M. (n=5 or 6). Basal and nicotinamide adenine dinucleotide phosphate (NADPH)-driven superoxide were measured in the aortas of the rats. NADPH (0.1 mM) was added to measure NADPH oxidase activity. Sham, sham-operated group; AC, aortic coarctation; TSA, TSA-treated sham-operated group; AC+TSA, TSA-treated aortic coarctation group. *p<0.05 (vs. sham group). #p<0.05 (vs. aortic coarctation group).
Mentions: We investigated the effect of TSA on blood pressure in sham and aortic coarctation-induced hypertensive rats. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) were significantly higher in aortic coarctation-induced hypertensive rats. Chronic treatment with TSA (0.5 mg/kg/day) for 7 days significantly reduced high arterial blood pressure induced by aortic coarctation (Fig. 1A). As shown in Fig. 1A, chronic treatment with TSA significantly reduced SBP in aortic coarctation rats (169.8±8.2 mmHg vs. 133.1±3.5 mmHg, p<0.05), but did not reduce SBP in sham rats (125.5±3.0 mmHg vs. 112.9±9.5 mmHg). Additionally, even though DBP and MAP were reduced in TSA-treated sham and aortic coarctation-rats, the anti-hypertensive effect of TSA in aortic coarctation rats was greater than that in sham-operated rats.

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