Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling

Wu, Jiunn Ren; Liou, Shu Fen; Lin, Shin Wha; Chai, Chee‐Yin; Dai, Zen Kong; Liang, Jyh Chong; Chen, Ing Jun; Yeh, Jwu‐Lai

doi:10.1016/j.phrs.2008.09.015

Cited by 42 publications

(40 citation statements)

References 21 publications

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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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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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“…Neointima formation and vascular remodeling are characteristics of early atherosclerotic lesions, and these pathological processes may involve EC dysfunction, VSMC proliferation and migration, and ECM deposition (20,21). Therefore, modulation of EC function and VSMC growth is of critical importance in the prevention and treatment of early atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

Zhang

Zhao

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

115

109

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Angiotensin-converting enzyme 2 (ACE2) is a newly discovered homolog of ACE whose actions oppose those of angiotensin II (AngII). However, the underlying mechanisms by which ACE2 effectively suppresses early atherosclerotic lesions remain poorly understood. Here, we show, both in vitro and in vivo, that ACE2 inhibited the development of early atherosclerotic lesions by suppressing the growth of vascular smooth muscle cells (VSMCs) and improving endothelial function. In a relatively large cohort animal study (66 rabbits), aortic segments transfected by Ad-ACE2 showed significantly attenuated fatty streak formation, neointimal macrophage infiltration, and alleviation of impaired endothelial function. Segments also showed decreased expression of monocyte chemoattractant protein 1, lectin-like oxidized low-density lipoprotein receptor 1, and proliferating cell nuclear antigen, which led to the delayed onset of atherosclerotic lesions. At the cellular level, ACE2 significantly modulated AngII-induced growth and migration in human umbilical vein endothelial cells and VSMCs. The antiatherosclerotic effect of ACE2 involved down-regulation of the ERKp38, JAK-STAT, and AngII-ROS-NF-κB signaling pathways and upregulation of the PI3K-Akt pathway. These findings revealed the molecular mechanisms of the antiatherosclerotic activity of ACE2 and suggested that modulation of ACE2 could offer a therapeutic option for treating atherosclerosis.atherosclerosis | endothelial cell | gene therapy | smooth muscle cell | signaling pathway A ccumulating evidence indicates that endothelial cell (EC) dysfunction and the proliferation and migration of vascular smooth muscle cells (VSMCs) are salient features of early atherosclerotic lesions, and that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis (1, 2). Angiotensin II (AngII) promotes EC dysfunction and VSMC proliferation and migration by increasing the expression of monocyte chemoattractant protein 1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), leading to aggravation of atherosclerotic lesions (3-5). Delivery of ACE inhibitors or AngII type 1 receptor (AT 1 R) blockers to limit AngII bioactivity is an effective approach against atherosclerosis.Recent studies show that endogenous levels of AngII are regulated by the opposing action of two carboxypeptidases, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). The latter is thought to counterbalance ACE by cleaving AngI into the inactive angiotensin 1-9 and cleaving AngII into the vasodilating and antiproliferative angiotensin 1-7 [Ang(1-7)]. ACE2 is thus considered a potential therapeutic target of RAS for the treatment of cardiovascular diseases by virtue of its key role in the formation of vasoprotective peptides from AngII (6-8). Our recent study using a rabbit atherosclerosis model showed that ACE2 overexpression stabilized aortic plaques at a late stage and attenuated the progression of early atherosclerotic lesions. These ther...

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“…Previous studies have shown that lercanidipine posses several vascular protections. [26][27][28] However, the impact of lercanidipine on CXCR7 signaling expression of EPCs and its relation to endothelial protection in hypertensive patients is unclear. We hypothesized that lercanidipine might facilitate the expression of CXCR7 signaling in EPCs, which contributes to EPC-mediated re-endothelialization after arterial injury.…”

Section: Hypertensionmentioning

confidence: 99%

CXCR7 Upregulation Is Required for Early Endothelial Progenitor Cell–Mediated Endothelial Repair in Patients With Hypertension

Zhang

Cao

et al. 2014

Hypertension

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Abstract-Dysfunction of early endothelial progenitor cells (EPCs) is responsible for impaired endothelial repair capacity after arterial injury in patients with hypertension. Here, we hypothesized that diminished signaling of CXC chemokine receptor 7 (CXCR7) contributes to the reduced EPC functions, and enhanced CXCR7 expression restores the capacities of EPCs from hypertensive patients. CXCR7 expression of EPCs from hypertensive patients was significantly reduced when compared with that from healthy subjects. Meanwhile, the phosphorylation of p38 mitogen-activated protein kinase, a downstream signaling of CXCR7, was elevated, which increased cleaved caspase-3 level of EPCs. CXCR7 gene transfer augmented CXCR7 expression and decreased the phosphorylation of p38 mitogen-activated protein kinase, which was paralleled to EPC functional upregulation of in vitro adhesion, antiapoptosis activities, and in vivo re-endothelialization capacity in a nude mouse model of carotid artery injury. The enhanced in vitro and in vivo functions of EPCs were markedly inhibited by neutralizing monoclonal antibody against CXCR7, which was blocked by p38 mitogen-activated protein kinase inhibitor SB203580. Downregulation of cleaved caspase-3 level induced by CXCR7 gene transfer or SB203580 pretreatment improved EPC functions. Furthermore, we found that lercanidipine, a dihydropyridine calcium channel antagonist, enhanced CXCR7 expression and facilitated in vitro and in vivo functions of EPCs. Our study demonstrated for the first time that diminished CXCR7 signal at least partially contributes to the reduced in vitro functions and in vivo re-endothelialization capacity of EPCs from hypertensive patients. Upregulation of CXCR7 expression induced by gene transfer or lercanidipine treatment may be a novel therapeutic target for increased endothelial repair capacity in

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Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling

Cited by 42 publications

References 21 publications

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

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

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

CXCR7 Upregulation Is Required for Early Endothelial Progenitor Cell–Mediated Endothelial Repair in Patients With Hypertension

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Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling

Cited by 42 publications

References 21 publications

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

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

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells

CXCR7 Upregulation Is Required for Early Endothelial Progenitor Cell–Mediated Endothelial Repair in Patients With Hypertension

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Product

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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

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