Figure - available from: Naunyn-Schmiedeberg's Archives of Pharmacology
This content is subject to copyright. Terms and conditions apply.
Effect of atorvastatin on CaCl2-induced aortic contraction. a Representative recording of CaCl2 (10 μM–5 mM)-induced concentration-dependent contraction in fresh aorta, and aorta cultured with or without 20 μM atorvastatin. b Atorvastatin enhanced vasoconstriction induced by CaCl2 (10 μM–5 mM) in aortic rings in organ culture. Data are shown as means ± S.E.M. (n = 6); one-way analysis of variance (ANOVA) was used for multiple groups followed by LSD and SNK test to compare individual means. *p < 0.05 vs. fresh control, #p < 0.05 vs. serum-free culture
Source publication
Statins are widely used in the treatment of hypercholesterolemia. Studies have demonstrated that statins could maintain vascular contractile function through inhibiting the transformation of vascular smooth muscle cells (VSMCs) from the contractile phenotype to the synthetic phenotype. However, the underlying mechanisms have not been fully elucidat...
Citations
Background
Thromboxane A2 (TXA2) participates in many pathophysiological processes of coronary artery disease. However, its mechanism of TXA2‐induced contraction in the coronary artery remains to be clarified.
Methods
Multi Myograph System was used to measure the isometric tension of the mouse coronary arteries and identify the effect and pathway of TXA2 analogues U46619. Confocal laser scanning microscopy was used to measure the intracellular calcium concentration ([Ca²⁺]i) in mouse coronary artery smooth muscle cells.
Results
Results from the experiment had shown that contraction in coronary artery was generated by U46619 in a concentration‐ dependent manner, which was completely abolished by a specific TXA2 receptor blocker, GR32191. PI‐PLC inhibitors U73122 and D609 and Rho‐Kinase inhibitor Y‐27632 can block the U46619 elicited coronary artery contraction in a dose‐dependent manner. Then, the vasoconstriction response to U46619 was obviously inhibited by two pan‐PKC inhibitors chelerythrine or Gӧ6983, and a selective PKCδ inhibitor rottlerin, but wasn’t blocked by a selective PKCζ inhibitor PKC‐PS or a selective PKCβ inhibitor hispidin. Meanwhile, the PKC activator PDBu‐induced vasoconstriction was significantly inhibited by 1 μM nifedipine,then mostly inhibited by 100 μM 2‐APB and 10 μM Y27632. We further found that the response to U46619 was inhibited respectively by three calcium channel blockers nifedipine, SKF96356 or 2‐APB in a concentration‐dependent manner. Although Store‐operated Ca²⁺ (SOC) channels generated the increase of [Ca²⁺]i in mouse coronary artery smooth muscle cells, SOC channels didn’t contribute to the vasoconstriction in mouse coronary arteries. Caffeine‐induced sarcoplasmic reticulum (SR) Ca²⁺ release could obviously induce coronal vasoconstriction. In addition, NPPB, a cell membrane Ca²⁺ activated C1⁻ channel blocker, could obviously inhibit the U46619‐induced vasoconstriction.
Conclusions
The U46619‐induced mouse coronary artery contraction was involved in the increase in [Ca²⁺]i mediated by Cav1.2, TRPC channels and SR release through the activation of G‐protein‐coupled TP receptors and the kinases signaling pathway in TP downstream proteins, while SOC channels didn’t participate in the vasoconstriction.
The renin-angiotensin system, one of the main regulators of vascular function, controls vasoconstriction, inflammation and vascular remodeling. Antagonistic actions of the counter-regulatory renin-angiotensin system, which include vasodilation, anti-proliferative, anti-inflammatory and anti-remodeling effects, have also been described. However, little is known about the direct effects of angiotensin-(1-9), a peptide of the counter-regulatory renin-angiotensin system, on vascular smooth muscle cells. Here, we studied the anti-vascular remodeling effects of angiotensin-(1-9), with special focus on the control of vascular smooth muscle cell phenotype. Angiotensin-(1-9) decreased blood pressure and aorta media thickness in spontaneously hypertensive rats. Reduction of media thickness was associated with decreased vascular smooth muscle cell proliferation. In the A7r5 VSMC cell line and in primary cultures of rat aorta smooth muscle cells, Angiotensin-(1-9) did not modify basal proliferation. However, angiotensin-(1-9) inhibited proliferation, migration and contractile protein decrease induced by platelet derived growth factor-BB. Moreover, angiotensin-(1-9) reduced Akt and FoxO1 phosphorylation at 30 min, followed by an increase of total FoxO1 protein content. Angiotensin-(1-9) effects were blocked by the AT2R antagonist PD123319, Akt-Myr overexpression and FoxO1 siRNA. These data suggest that angiotensin-(1-9) inhibits vascular smooth muscle cell dedifferentiation by an AT2R/Akt/FoxO1-dependent mechanism.
