Effect of the New Calcium Antagonist Lercanidipine and Its Enantiomers on the Migration and Proliferation of Arterial Myocytes

Corsini, Alberto; Bonfatti, M.; Quarato, P.; Accomazzo, Maria Rosa; Raiteri, M.; Sartani, A.; Testa, Rodolfo; Nicosia, S.; Paoletti, Rodolfo; Fumagalli, R.

doi:10.1097/00005344-199611000-00012

Cited by 47 publications

(32 citation statements)

References 40 publications

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“…hSMCs were cultured using the SMC Growth Medium 2 Bullet Kit , purchased from BioWhittaker Inc. Mouse primary aortic SMCs (mSMCs) were prepared from aortas of 8-to 12-week-old PPARα +/+ or PPARα -/-mice on Sv/129 or C57BL/6J genetic backgrounds or of p16 +/+ or p16 -/-mice on a C57BL/6J genetic background as described (57) and were studied between the third and twelfth passages. mSMCs were cultured in DMEM supplemented with 10% FCS and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

Gizard¹,

Amant²,

Barbier³

et al. 2005

J. Clin. Invest.

148

133

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Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARα is a nuclear receptor controlling lipid metabolism and inflammation, but its role in the regulation of SMC growth remains to be established. Here, we show that PPARα controls SMC cell-cycle progression at the G 1 /S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16 INK4a (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARα activates p16 gene transcription by both binding to a canonical PPAR-response element and interacting with the transcription factor Sp1 at specific proximal Sp1-binding sites of the p16 promoter. In a carotid arterial-injury mouse model, p16 deficiency results in an enhanced SMC proliferation underlying intimal hyperplasia. Moreover, PPARα activation inhibits SMC growth in vivo, and this effect requires p16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARα inhibits SMC proliferation through p16. Thus, the PPARα/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.

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Section: Methodsmentioning

confidence: 99%

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

Gizard¹,

Amant²,

Barbier³

et al. 2005

J. Clin. Invest.

148

133

View full text Add to dashboard Cite

show abstract

“…One relevant exception may be represented by smooth muscle cells, in which Ca 2+ VOCs are expressed at relatively high densities, and that can actively proliferate in inflammation and hypertrophic growth of blood vessels and other organs; in this case, too, most of the evidence is indirect, based on the effects of VOCs blockers [see e.g. 4,[27][28][29][30]. Expression of L-type channels has been associated with long-term exposure to transforming growth factor β (TGFβ) and ensuing transformation of hepatic stellate cells [31].…”

Section: Voltage Operated Channels (Vocs)mentioning

confidence: 99%

Intracellular Calcium, Endothelial Cells and Angiogenesis

Munaron

2006

PRA

124

117

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The proliferation and motility of vascular endothelial cells (ECs) are critical steps in angiogenesis and are strictly controlled by different extracellular signals. Among mitogens, peptides binding to tyrosine kinase receptors (i.e. VEGFs and FGFs) are well known and are released by several cell types, including ECs and tumor cells. The binding of mitogens to their specific receptors triggers intracellular signaling cascades, involving a number of messengers working in a sort of network. In particular, in this review we describe the increases of calcium levels in the cytosol, a universal, evolutionary conserved and highly versatile signal involved in the regulation of EC's proliferation and motility. Most mitogens, including angiogenic factors, generate cytosolic calcium rises through two mechanisms: entry from extracellular medium, through the opening of calcium permeable channels in the plasma membrane, or release from intracellular organelles (mainly endoplasmic reticulum, ER). Calcium entry, the main topic of this review, can be dependent on previously IP(3)-activated emptying of calcium stores (store-dependent or capacitative calcium entry--CCE), or independent on it (non capacitative calcium entry, NCCE). The intracellular pathways underlying calcium entry are under investigation and recently arachidonic acid (AA) and nitric oxide (NO) metabolism have been suggested to play a key role, at least in some cell types. Even if some calcium entry blockers are under clinical trial with encouraging results, a better knowledge about the molecular nature of calcium channels and their intracellular regulation, together with a more detailed description of spatiotemporal dynamics of intracellular calcium events, could lead to new and more specific strategies in therapeutical approach to cancer progression and angiogenesis.

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“…88,89 Similarly, experiments with rat aortic VSMCs suggested that in contrast to nifedipine, amlodipine-elicited inhibition of serum-, thrombin-, and basic fibroblast growth factor-triggered VSMC proliferation involved mechanisms independent of CCB properties. 84 In support of this hypothesis, amlodipine has been reported to inhibit thrombin-induced Ca 2ϩ mobilization from thapsigargin-sensitive, internal Ca 2ϩ stores; this effect could not be obtained with isradipine, diltiazem, and verapamil.…”

Section: Effect On Calcium Signalingmentioning

confidence: 99%

Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists

Mason

Marché

Hintze

2003

ATVB

157

117

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Abstract-Calcium channel blockers (CCBs) were developed as vasodilators, and their use in cardiovascular disease treatment remains largely based on that mechanism of action. More recently, with the evolution of second-and third-generation CCBs, pleiotropic effects have been observed, and at least some of CCBs' benefit is attributable to these mechanisms. Understanding these effects has contributed greatly to elucidating disease mechanisms and the rationale for CCB use. Furthermore, this knowledge might clarify why drugs are useful in some disease states, such as atherosclerosis, but not in others, such as heart failure. Although numerous drugs used in the treatment of vascular disease, including statins and angiotensin-converting-enzyme inhibitors, have well-described pleiotropic effects universally accepted to contribute to their benefit, little attention has been paid to CCBs' potentially similar effects.Accumulating evidence that at least 1 CCB, amlodipine, has pharmacologic actions distinct from L-type calcium channel blockade prompted us to investigate the pleiotropic actions of amlodipine and CCBs in general. There are several areas of research; foci here are (1) the physicochemical properties of amlodipine and its interaction with cholesterol and oxidants; (2) the mechanism by which amlodipine regulates NO production and implications; and (3) amlodipine's role in controlling smooth muscle cell proliferation and matrix formation.

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Effect of the New Calcium Antagonist Lercanidipine and Its Enantiomers on the Migration and Proliferation of Arterial Myocytes

Cited by 47 publications

References 40 publications

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

PPARα inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a

Intracellular Calcium, Endothelial Cells and Angiogenesis

Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists

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