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Valsartan decreases platelet activity and arterial thrombotic events in elderly patients with hypertension.

Wu F, Wang HY, Cai F, Wang LJ, Zhang FR, Chen XN, Yang Q, Jiang MH, Wang XF, Shen WF - Chin. Med. J. (2015)

Bottom Line: PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001).During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002).Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai 200025, China.

ABSTRACT

Background: Angiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Methods: Two-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA).

Results: PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).

Conclusions: AT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

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Angiotensin II (Ang II) induced the expression of cyclooxygenase-2 (COX-2) and phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) in human aortic endothelial cells. (a) mRNA expression of COX-2 according to the concentration of Ang II. *P < 0.01. NS: not significant. (b) mRNA expression of COX-2 according to the time induced by Ang II (100 nmol/L). *P < 0.01 vs. control. †P < 0.001 vs. control. (c) Protein expression of COX-2 induced by Ang II (100 nmol/L). (d) Protein expression of p38 mitogen-activated protein kinase (p38MAPK), phosphorylation of p38MAPK, NF-kB and phosphorylation of NF-kB induced by Ang II. (e) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 mRNA expression induced by Ang II for 1 h; †P < 0.001. (f) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 protein expression induced by Ang II for 2 h. C means control group, SB + Ang means SB203580 + Ang II group, JSH + Ang means JSH-23 + Ang II group. Data represent the mean ± standard deviation (n = 3).
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Figure 2: Angiotensin II (Ang II) induced the expression of cyclooxygenase-2 (COX-2) and phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) in human aortic endothelial cells. (a) mRNA expression of COX-2 according to the concentration of Ang II. *P < 0.01. NS: not significant. (b) mRNA expression of COX-2 according to the time induced by Ang II (100 nmol/L). *P < 0.01 vs. control. †P < 0.001 vs. control. (c) Protein expression of COX-2 induced by Ang II (100 nmol/L). (d) Protein expression of p38 mitogen-activated protein kinase (p38MAPK), phosphorylation of p38MAPK, NF-kB and phosphorylation of NF-kB induced by Ang II. (e) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 mRNA expression induced by Ang II for 1 h; †P < 0.001. (f) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 protein expression induced by Ang II for 2 h. C means control group, SB + Ang means SB203580 + Ang II group, JSH + Ang means JSH-23 + Ang II group. Data represent the mean ± standard deviation (n = 3).

Mentions: The expression of COX-2 mRNA in HCACEs was dose-and time-dependently increased after stimulation with Ang II, with maximum expression (4 times higher than control, P < 0.001) 1 h after stimulation with Ang II (100 nmol/L) [Figure 2a and 2b]. At protein level, the peak expression of COX-2 occurred 2 hours after Ang II stimulation (100 nmol/L) [Figure 2c]. Ang II also increased the phosphorylation of p38MAPK (p-p38MAPK) and NF-kB (p-NF-kB) [Figure 2d]; when pretreating HAECs with p38MAPK inhibitor SB203580 (25 µmol/L) and NF-kB inhibitor JSH-23 (25 µmol/L), the expression of COX-2 was significantly decreased at both mRNA and protein levels [Figure 2e and f].


Valsartan decreases platelet activity and arterial thrombotic events in elderly patients with hypertension.

Wu F, Wang HY, Cai F, Wang LJ, Zhang FR, Chen XN, Yang Q, Jiang MH, Wang XF, Shen WF - Chin. Med. J. (2015)

Angiotensin II (Ang II) induced the expression of cyclooxygenase-2 (COX-2) and phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) in human aortic endothelial cells. (a) mRNA expression of COX-2 according to the concentration of Ang II. *P < 0.01. NS: not significant. (b) mRNA expression of COX-2 according to the time induced by Ang II (100 nmol/L). *P < 0.01 vs. control. †P < 0.001 vs. control. (c) Protein expression of COX-2 induced by Ang II (100 nmol/L). (d) Protein expression of p38 mitogen-activated protein kinase (p38MAPK), phosphorylation of p38MAPK, NF-kB and phosphorylation of NF-kB induced by Ang II. (e) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 mRNA expression induced by Ang II for 1 h; †P < 0.001. (f) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 protein expression induced by Ang II for 2 h. C means control group, SB + Ang means SB203580 + Ang II group, JSH + Ang means JSH-23 + Ang II group. Data represent the mean ± standard deviation (n = 3).
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Figure 2: Angiotensin II (Ang II) induced the expression of cyclooxygenase-2 (COX-2) and phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) in human aortic endothelial cells. (a) mRNA expression of COX-2 according to the concentration of Ang II. *P < 0.01. NS: not significant. (b) mRNA expression of COX-2 according to the time induced by Ang II (100 nmol/L). *P < 0.01 vs. control. †P < 0.001 vs. control. (c) Protein expression of COX-2 induced by Ang II (100 nmol/L). (d) Protein expression of p38 mitogen-activated protein kinase (p38MAPK), phosphorylation of p38MAPK, NF-kB and phosphorylation of NF-kB induced by Ang II. (e) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 mRNA expression induced by Ang II for 1 h; †P < 0.001. (f) The effect of SB203580 (25 nmol/L) and JSH-23 (25 nmol/L) on COX-2 protein expression induced by Ang II for 2 h. C means control group, SB + Ang means SB203580 + Ang II group, JSH + Ang means JSH-23 + Ang II group. Data represent the mean ± standard deviation (n = 3).
Mentions: The expression of COX-2 mRNA in HCACEs was dose-and time-dependently increased after stimulation with Ang II, with maximum expression (4 times higher than control, P < 0.001) 1 h after stimulation with Ang II (100 nmol/L) [Figure 2a and 2b]. At protein level, the peak expression of COX-2 occurred 2 hours after Ang II stimulation (100 nmol/L) [Figure 2c]. Ang II also increased the phosphorylation of p38MAPK (p-p38MAPK) and NF-kB (p-NF-kB) [Figure 2d]; when pretreating HAECs with p38MAPK inhibitor SB203580 (25 µmol/L) and NF-kB inhibitor JSH-23 (25 µmol/L), the expression of COX-2 was significantly decreased at both mRNA and protein levels [Figure 2e and f].

Bottom Line: PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001).During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002).Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Ruijin Hospital, Jiao Tong University School of Medicine, Shanghai 200025, China.

ABSTRACT

Background: Angiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Methods: Two-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA).

Results: PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).

Conclusions: AT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

Show MeSH
Related in: MedlinePlus