Distinct effects of amlodipine treatment on vascular elastocalcinosis and stiffness in a rat model of isolated systolic hypertension

Essalihi, Rachida; Zandvliet, Maarten L.; Moreau, Simon; Gilbert, Liz-Ann; Bouvet, Céline; Lenoel, Cyrille; Nekka, Fahima; McKee, Marc D.; Moreau, Pierre

doi:10.1097/hjh.0b013e328255e906

Cited by 24 publications

(12 citation statements)

References 34 publications

(38 reference statements)

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“…In the large conduit arteries, L-type Ca 2+ channels are important determinants of their mechanical properties and compliance, which are such that blood pressure and flow are propagated between the heart and arterioles and that thereby pulsatile flow is transformed into steady flow due to the "windkessel" effect (Westerhof et al, 2009). For example, CaBs increase vascular compliance of large elastic vessels and may be of importance for the pathogenesis and prognosis of cardiovascular complications such as atherosclerosis, left ventricular hypertrophy and heart failure (Bellien et al, 2010;Belz, 1995;Essalihi et al, 2007;Safar et al, 1989;Slama et al, 1995;Vayssettes-Courchay et al, 2011). Further evidence for a role of L-type Ca 2+ channels in atherosclerosis was obtained in carotid and femoral VSMCs, where the L-type Ca 2+ channel gene expression differs between atherosclerotic versus non-atherosclerotic regions (Tiwari et al, 2006).…”

Section: Introductionmentioning

confidence: 84%

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

Fransen¹,

Hove²,

Langen³

et al. 2012

Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues - From Molecules to Humans

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Section: Introductionmentioning

confidence: 84%

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

Fransen¹,

Hove²,

Langen³

et al. 2012

Current Basic and Pathological Approaches to the Function of Muscle Cells and Tissues - From Molecules to Humans

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“…However, only 28 days of doxycycline prevented the PWV increase, suggesting that not only elastin degradation and calcification are implicated in arterial stiffness, but also fibrosis could intervene in this process. 34 As mentioned earlier, degraded elastin presents an increased affinity for calcium. However, extracellular matrix degradation by elastases also induces the release of soluble elastin peptides and TGF-␤ 13 that can influence the process of elastocalcinosis.…”

Section: Discussionmentioning

confidence: 99%

Sequential Activation of Matrix Metalloproteinase 9 and Transforming Growth Factor β in Arterial Elastocalcinosis

Bouvet

Moreau

Blanchette

et al. 2008

ATVB

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Objective-Isolated systolic hypertension is associated with increased elastase activity, vascular calcification, and vascular stiffness. We sought to determine the importance of elastase activity and matrix degradation in the development of elastocalcinosis. Methods and Results-Elastocalcinosis was induced in vivo and ex vivo using warfarin. Hemodynamic parameters, calcium deposition, elastin degradation, transforming growth factor (TGF)-␤ signaling, and elastase activity were evaluated at different time points in the in vivo model. Metalloproteinases, serine proteases, and cysteine proteases were blocked to measure their relative implication in elastin degradation. Gradual elastocalcinosis was obtained, and paralleled the elastin degradation pattern. Matrix metalloproteinase (MMP)-9 activity was increased at 5 days of warfarin treatment, whereas TGF-␤ signaling was increased at 7 days. Calcification was significantly elevated after 21 days. Blocking metalloproteinases activation with doxycycline and TGF-␤ signaling with SB-431542 were able to prevent calcification. Conclusions-Early MMP-9 activation precedes the increase of TGF-␤ signaling, and overt vascular elastocalcinosis and stiffness. Modulation of matrix degradation could represent a novel therapeutic avenue to prevent the gradual age-related stiffening of large arteries, leading to isolated systolic hypertension. Elastocalcinosis is characterized by a deposition of hydroxyapatite on the elastic lamellae of arteries. It occurs independently of atherosclerosis. 2 Until recently, it was considered as a passive process, taking place with time. However, several studies demonstrated that vascular calcification is an active phenomenon controlled by serum and matrix proteins, such as matrix Gla protein. 3 Moreover, it involves phenotypic changes of vascular smooth muscle cells with the expression of bone-related proteins. 4 Aging is associated with an increased collagen/elastin ratio explained in part by an enhanced degradation of elastin. 5,6 Indeed, elastase activity, mainly endopeptidases, including cysteine proteases, serine proteases, and metalloproteinases, is increased with age in human aortas. 7 In the context of aging and vascular calcification, metalloproteinases, especially matrix metalloproteinases (MMPs), have been thoroughly studied. Investigations on the genetic mutations of MMPs demonstrated its contribution to age-related large artery stiffening. 8,9 Furthermore, enhanced MMP-9 and MMP-2 levels and serum elastase activity were observed in patients with ISH and correlated independently with PWV. 10 In 2000, Vyavahare et al showed for the first time that elastin calcification was blunted by a site specific delivery of MMP inhibitor. 11 Moreover, Qin et al demonstrated, in an animal model, that matrix metalloproteinase inhibition with doxycycline and GM6001 decreased hydroxyapatite accumulation in the aorta. 12 These results suggest that MMPs and elastin degradation are involved in MEC.Elastin degradation induces the release of soluble elastin pep...

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“…Although the precise pathophysiological mechanisms of arterial stiffness and vascular calcification are not yet fully understood, passive calcium deposition and active modification of osteotrophic regulators such as osteoprotegerin and fetuin-A are thought to play important roles in this process [4-6]. …”

Section: Introductionmentioning

confidence: 99%

Effects of Lowering Dialysate Calcium Concentrations on Arterial Stiffness in Patients Undergoing Hemodialysis

Kim

Moon

Park

et al. 2011

Korean J Intern Med

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Background/AimsWe assessed changes in hemodynamic and arterial stiffness parameters following reductions of dialysate calcium concentrations in patients undergoing hemodialysis.MethodsIn this prospective study, 20 patients on maintenance hemodialysis (10 females, 10 males) with dialysate calcium concentrations of 1.75 mmol/L were enrolled. At the start of the study, the dialysate calcium level was lowered to 1.50 mmol/L. Serial changes in biochemical, hemodynamic, and arterial stiffness parameters, including pulse wave velocity (PWV) and augmentation index (AIx), were assessed every 2 months for 6 months. We also examined changes in the calcification-inhibitory protein, serum fetuin-A.ResultsDuring the 6-month study period, serum total calcium and ionized calcium decreased consistently (9.5 ± 1.0 to 9.0 ± 0.7, p = 0.002 vs. 1.3 ± 0.1 to 1.1 ± 0.1, p = 0.035). Although no apparent changes in blood pressure were observed, heart-femoral PWW (hf-PWV) and AIx showed significant improvement (p = 0.012, 0.043, respectively). Repeated-measures ANOVA indicated a significant effect of lowering dialysate calcium on hf-PWV (F = 4.58, p = 0.004) and AIx (F = 2.55, p = 0.049). Accompanying the change in serum calcium, serum fetuin-A levels significantly increased (95.8 ± 45.8 pmol/mL at baseline to 124.9 ± 82.2 pmol/mL at 6 months, p = 0.043).ConclusionsLowering dialysate calcium concentration significantly improved arterial stiffness parameters, which may have been associated with upregulation of serum fetuin-A.

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Distinct effects of amlodipine treatment on vascular elastocalcinosis and stiffness in a rat model of isolated systolic hypertension

Cited by 24 publications

References 34 publications

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

Sequential Activation of Matrix Metalloproteinase 9 and Transforming Growth Factor β in Arterial Elastocalcinosis

Effects of Lowering Dialysate Calcium Concentrations on Arterial Stiffness in Patients Undergoing Hemodialysis

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