Nifedipine inhibits vascular smooth muscle cell proliferation and reactive oxygen species production through AMP-activated protein kinase signaling pathway

Sung, Jin Young; Choi, Hyoung Chul

doi:10.1016/j.vph.2011.06.001

Cited by 31 publications

(19 citation statements)

References 31 publications

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“…AMPK, as an energy sensor, is ubiquitously expressed in vascular cells, and exerts anti-atherosclerotic effects associated to suppression of inflammatory responses [44-46]. The beneficial effects of adiponectin on cardiovascular diseases are expected to be partially mediated by activation of AMPK signalling pathway [47].…”

Section: Discussionmentioning

confidence: 99%

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Sun¹,

Zhu²,

Lin³

et al. 2017

Cell Physiol Biochem

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Background /Aims: Accumulating evidence indicates that endothelial inflammation is one of the critical determinants in pathogenesis of atherosclerotic cardiovascular disease. Our previous studies had demonstrated that Vaccariae prevented high glucose or oxidative stress-triggered endothelial dysfunction in vitro. Very little is known about the potential effects of hypaphorine from Vaccariae seed on inflammatory response in endothelial cells. Methods: In the present study, we evaluated the anti-inflammatory effects of Vaccariae hypaphorine (VH) on lipopolysaccharide (LPS)-challenged endothelial EA.hy926 cells. The inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein 1 (MCP-1) and vascular cellular adhesion molecule-1 (VCAM-1) were measured by real-time PCR (RT-PCR). The expressions of adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), toll-like receptor 4 (TLR4), peroxisome proliferator-activated receptor γ (PPARγ) were detected by Western blotting or immunofluorescence. Results: We showed that LPS stimulated the expressions of TNF-α, IL-1β, MCP-1, VCAM-1 and TLR4, but attenuated the phosphorylation of AMPK and ACC as well as PPARγ protein levels, which were reversed by VH pretreatment. Moreover, we observed that LPS-upregulated TLR4 protein expressions were inhibited by PPARγ agonist pioglitazone, and the downregulated PPARγ expressions in response to LPS were partially restored by knockdown of TLR4. The negative regulation loop between TLR4 and PPARγ response to LPS was modulated by AMPK agonist AICAR (5-Aminoimidazole-4-carboxamide riboside or acadesine) or A769662. Conclusions: Taken together, our results suggested that VH ameliorated LPS-induced inflammatory cytokines production in endothelial cells via inhibition of TLR4 and activation of PPARγ, dependent on AMPK signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Sun¹,

Zhu²,

Lin³

et al. 2017

Cell Physiol Biochem

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“…Inhibition of VDCC with nifedipine and other VDCC blockers significantly attenuates smooth muscle cell proliferation cultured in media containing growth factors and serum (30,49,55), which would indicate that Ca 2ϩ influx through L-type and T-type VDCC is required for smooth muscle cell proliferation. Silenced expression of T-type VDCC in human PASMC was also shown to significantly attenuate proliferation (44), providing further evidence that T-type channels are essential in controlling prolif- eration.…”

Section: Discussionmentioning

confidence: 99%

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2

Wan

Yamamura

Zimnicka

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hypoxia-induced pulmonary hypertension (HPH) is characterized by sustained pulmonary vasoconstriction and vascular remodeling, both of which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ]cyt) is a major trigger for pulmonary vasoconstriction and an important stimulus for cell proliferation in PASMCs. Ca 2ϩ influx through voltage-dependent Ca 2ϩ channels (VDCC) is an important pathway for the regulation of [Ca 2ϩ ]cyt. The potential role for L-and T-type VDCC in the development of HPH is still unclear. Using a hypoxic-induced pulmonary hypertension mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 wk, and high-K ϩ -and U-46619-induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high-K ϩ -and U-46619-induced Ca 2ϩ influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high-K ϩ -and U-46619-induced contraction of mesenteric artery (MA). Compared with MA, PA displayed higher expression of calcium channel voltagedependent L-type ␣ 1C-subunit (Cav1.2) and T-type ␣1H-subunit (Ca v3.2) upon exposure to chronic hypoxia. In conclusion, both L-type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Ca v1.2 and Cav3.2.hypoxia; voltage-dependent calcium ion channel; pulmonary artery; mouse; calcium channel voltage-dependent L-type ␣ 1C-subunit; calcium channel voltage-dependent T-type ␣ 1H-subunit PERSISTENT HYPOXIA INDUCES vasoconstriction of small pulmonary arteries (PA) and vascular remodeling, including smooth muscle cell hypertrophy and hyperplasia, eventually resulting in hypoxic pulmonary hypertension (HPH). Pulmonary hypertension associated with hypoxia belongs to the third group in the classification of pulmonary hypertension according to the proceedings of the Fourth World Symposium on Pulmonary Hypertension at Dana Point 2008 (17). Over time, HPH causes right ventricle hypertrophy, right ventricular failure, and death (1, 37). Pulmonary hypertension related to chronic obstructive pulmonary disease (COPD) is one of the most common forms of HPH and is significantly associated with increased mortality (8, 36). Currently, there is no specific therapy for pulmonary hypertension associated with COPD, which provides motivation for researchers to understand the pathogenic mechanisms of HPH.Sustained pulmonary vasoconstriction and vascular remodeling are the predomina...

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“…In contrast, no change in the potent relaxation activity of nifedipine, another type of VDCC blocker, between young and aged SHR (and WKY) was found irrespective to their different VDCC expressions (Figures 5 and 6). This might be explained by alternative roles of nifedipine in vasorelaxation signaling pathways by activating AMP-activated protein kinase [29] and endothelial NO synthase [30]. However, further study on the relationship between activation of relaxation-signaling pathways by VDCC blockers and aging is needed.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of L-Type Ca2+ Channel Expression and Vasomotor Response in the Aorta with Age in Both Wistar-Kyoto and Spontaneously Hypertensive Rats

et al. 2014

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Age-related vascular diseases are induced by vascular dysfunction, which involves changes in the vasomotor response. The voltage-dependent L-type calcium channel (VDCC) protein is involved in the regulation of vessel function (contraction/relaxation action). In the present study, we evaluated age-related vasomotor function and expression of the signal-related target proteins, including VDCC, using thoracic aorta from both 8- and 40-week old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). In contraction experiments using aortic rings, vasomotor responses of both phenylephrine-induced contraction and acetylcholine-induced relaxation were significantly attenuated with age in SHR, whereas WKY did not lose activity with age. Contraction induced by angiotensin II was impaired only for the 40-week old SHR among all the rat groups tested, although enhanced AT1R/reduced AT2R expression with age was observed for both WKY and SHR. In contrast, a vasomotor responsiveness to Bay K 8644 (a VDCC agonist) at the initial contraction phase was significantly attenuated in both 40-week WKY and SHR with significant reduction of VDCC protein expression. The reduced VDCC expression in 40-week old rats significantly lowered the relaxation activity of VDCC blockers, such as verapamil and Trp-His, but did not affect that of nifedipine. Taken together, we provided the first evidence that aging caused a reduction of VDCC expression in rat aorta, irrespective of the rat strain, along with diminishment of the therapeutic potential of VDCC blockers.

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Nifedipine inhibits vascular smooth muscle cell proliferation and reactive oxygen species production through AMP-activated protein kinase signaling pathway

Cited by 31 publications

References 31 publications

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2

Attenuation of L-Type Ca2+ Channel Expression and Vasomotor Response in the Aorta with Age in Both Wistar-Kyoto and Spontaneously Hypertensive Rats

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Nifedipine inhibits vascular smooth muscle cell proliferation and reactive oxygen species production through AMP-activated protein kinase signaling pathway

Cited by 31 publications

References 31 publications

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Interactions of TLR4 and PPARγ, Dependent on AMPK Signalling Pathway Contribute to Anti-Inflammatory Effects of Vaccariae Hypaphorine in Endothelial Cells

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2

Attenuation of L-Type Ca2+ Channel Expression and Vasomotor Response in the Aorta with Age in Both Wistar-Kyoto and Spontaneously Hypertensive Rats

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Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2