Pulsatile Mechanical Pressure Promotes Angiotensin-Converting Enzyme Expression in Aortic Smooth Muscle Cells

Iizuka, Kenji; Machida, Takuji; Kawaguchi, Hideaki; Hirafuji, Masahiko

doi:10.1007/s10557-008-6118-7

Cited by 17 publications

(20 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mechanical stress led to an increase in VSMC Ang II by elevation of ACE expression, and it increased calpain activation, seeming to counteract VSMC apoptosis by degradation of p53. 25,26 We observed a correlation between aortic diameter and ␣-2 spectrin cleavage (see the online-only Data Supplement). Because mechanical stress increases with aortic diameter, elevated calpain activity may be the result of augmented wall stress.…”

Section: Discussionmentioning

confidence: 79%

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

et al. 2009

View full text Add to dashboard Cite

Background-Marfan syndrome (MFS) is a heritable disorder of connective tissue, affecting principally skeletal, ocular, and cardiovascular systems. The most life-threatening manifestations are aortic aneurysm and dissection. We investigated changes in the proteome of aortic media in patients with and without MFS to gain insight into molecular mechanisms leading to aortic dilatation. Methods and Results-Aortic samples were collected from 46 patients. Twenty-two patients suffered from MFS, 9 patients had bicuspid aortic valve, and 15 patients without connective tissue disorder served as controls. Aortic media was isolated and its proteome was analyzed in 12 patients with the use of 2-dimensional difference gel electrophoresis and mass spectrometry. We found higher amounts of filamin A C-terminal fragment, calponin 1, vinculin, microfibrilassociated glycoprotein 4, and myosin-10 heavy chain in aortic media of MFS aneurysm samples than in controls.Regulation of filamin A C-terminal fragmentation was validated in all patient samples by immunoblotting. Cleavage of filamin A and the calpain substrate spectrin was increased in the MFS and bicuspid aortic valve groups. Extent of cleavage correlated positively with calpain 2 expression and negatively with the expression of its endogenous inhibitor calpastatin. Conclusions-Our observation demonstrates for the first time upregulation of the C-terminal fragment of filamin A in dilated aortic media of MFS and bicuspid aortic valve patients. In addition, our results present evidence that the cleavage of filamin A is highly likely the result of the protease calpain. Increased calpain activity might explain, at least in part, histological alterations in dilated aorta. Key Words: aneurysm Ⅲ aorta Ⅲ calpain Ⅲ Marfan syndrome Ⅲ proteomics M arfan syndrome (MFS) is a disorder of connective tissue caused by mutations in the fibrillin-1 gene (FBN-1) that may lead to abnormal regulation of transforming growth factor-␤ (TGF-␤) signaling. 1 Clinical manifestation implies principally the cardiovascular, skeletal, and ocular systems, and other systems such as skin, lung, and dura may also be affected. Cardiovascular defects involve dilatation of the ascending aortic root leading to aortic aneurysm and dissection, which are the main cause of morbidity and mortality in MFS, and mitral valve prolapse with or without regurgitation. 2 Clinical Perspective on p 991Molecular mechanisms of aneurysm formation and its treatment are the subject of intensive research. Three key proteins seem to directly contribute to aneurysm formation. First, defective fibrillin-1 is thought to alter targeting and sequestration of TGF-␤, leading to increased TGF-␤ activity. 1 Blocking TGF-␤ activity with antagonists such as TGF-␤-neutralizing antibodies prevents aneurysm formation in a mouse model of MFS. 3 Second, angiotensin II (Ang II) is upregulated in MFS. 4 Treatment of patients with Ang II type 1 (AT 1 ) receptor (AT 1 R) blocker or angiotensin-converting enzyme (ACE) inhibitors reduces progression of aortic d...

show abstract

Section: Discussionmentioning

confidence: 79%

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Under pressure, angiotensin the brain, heart, kidney, and vascular wall (3,7). Vascular smooth muscle is known to express renin, angiotensinogen, the angiotensin II AT 1 receptor, and angiotensin-converting enzyme (ACE) (6,13). A diet containing n-3 polyunsaturated fatty acids including docosahexaenoic acid (DHA) and eicosapentaenoic acid is well known to protect against several types of cardiovascular diseases: myocardial infarction, arrhythmia, atherosclerosis, and hypertension (11,29).…”

Section: Resultsmentioning

confidence: 99%

“…A pulsatile pressureloading apparatus that we designed was utilized in the experiments, as described previously (13,21). In DISCUSSION Hypertension is a major risk factor for atherosclerosis, which has a role in the pathogenesis of cardiovascular and cerebrovascular diseases.…”

Section: Methodsmentioning

confidence: 99%

“…While shear stress mainly affects vascular endothelial cells, pressure mainly acts on vascular smooth muscle cells (VSMCs). We previously demonstrated that static and pulsatile mechanical pressure stresses, which simulate systolic hypertension, promote proliferation of cultured human VSMCs (13,14). Excessive proliferation of VSMCs is also induced by various cytokines and growth factors, such as angiotensin II and platelet-derived growth factors (34).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

<b>Docosahexaenoic acid suppresses angiotensin II-induced A7r5 vascular smooth muscle cell proliferation and migration under pulsatile pressure str</b><b>ess </b>

Machida¹,

Yutani²,

Goto³

et al. 2018

Biomed. Res.

Self Cite

View full text Add to dashboard Cite

Elevated mechanical stress applied to vascular walls is well known to modulate vascular remodeling and plays a part in the pathogenesis of atherosclerosis. On the other hand, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has been shown to protect against several types of cardiovascular diseases including atherosclerosis and hypertension. The aim of this study was to clarify the effect of pulsatile pressure stress and DHA on angiotensin II-induced proliferation and migration in A7r5 vascular smooth muscle cells (VSMCs). Pulsatile pressure of between 80 and 160 mmHg was repeatedly applied to VSMCs at a frequency of 4 cycles per min using an apparatus that we developed. Cell proliferation and migration were evaluated using a live cell movie analyzer. Application of pulsatile pressure stress for 24 h significantly increased cell proliferation. Angiotensin II also significantly increased cell proliferation in the presence or absence of pressure stress. DHA significantly inhibited angiotensin II-induced cell proliferation regardless of the pressure load. Angiotensin II significantly induced cell migration regardless of the pulsatile pressure load. Pulsatile pressure stress alone slightly, but not significantly, induced cell migration. DHA inhibited angiotensin II-induced VSMC proliferation and migration under abnormal pressure conditions. Pressure stress tended to induce extracellular signal-regulated kinase (ERK) phosphorylation in the absence of angiotensin II, whereas it significantly induced ERK phosphorylation in the presence of angiotensin II. However, the pressure-induced ERK phosphorylation was not observed in the DHA-treated VSMCs. Our findings may contribute to the understanding of the beneficial effect of DHA on various cardiovascular disorders.Although the normal mechanical stress applied to vascular walls contributes to the maintenance of vascular homeostasis, excessive stress is well known to modulate vascular remodeling and plays a role in the pathogenesis of atherosclerosis. The mechanical factors applied to vascular walls can be divided into the following three factors: stretch, shear stress, and pressure. While shear stress mainly affects vascular endothelial cells, pressure mainly acts on vascular smooth muscle cells (VSMCs). We previously demonstrated that static and pulsatile mechanical pressure stresses, which simulate systolic hypertension, promote proliferation of cultured human VSMCs (13,14). Excessive proliferation of VSMCs is also induced by various cytokines and growth factors, such as angiotensin II and platelet-derived growth factors (34). In particular, a number of studies have revealed the mechanisms of VSMC proliferation and migration induced by angiotensin II (19,26). The renin-angiotensin system is known to exist not only in the circulation but also in local tissues including

show abstract

“…8 In the present study, we used this device to show the effect on the expression of ACE2 and the localization of ACE2 in human aortic endothelial cells (HAEC) when cells were exposed to pulsatile-mechanical pressure stress in the presence or absence of Ang II. In so doing, we tested the hypothesis of possible beneficial actions of a calcium channel blocker in an experimental setting.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II reduces membranous angiotensin-converting enzyme 2 in pressurized human aortic endothelial cells

Iizuka

Kusunoki

Machida

et al. 2009

J Renin Angiotensin Aldosterone Syst

Self Cite

View full text Add to dashboard Cite

Introduction. We applied pressure stress to human aortic endothelial cells (HAEC) and investigated whether mechanical pressure stress and/or angiotensin II (Ang II) affected angiotensin-converting enzyme (ACE) 2. We then tested whether the administration of nifedipine had a demonstrable and possibly beneficial effect. Methods. A pulsatile atmospheric pressure with or without Ang II was loaded on HAECs. The expression of ACE2 was studied by immunoblots and reverse transcription/real-time polymerase chain reaction. Results. The pulsatile mechanical pressure increased the expression of ACE2 mRNA by approximately 80%. Supplementation of Ang II (1 mM) with pulsatile mechanical pressure decreased the expression of ACE2 mRNA by approximately 54%. Pulsatile atmospheric pressure increased ACE2 protein, but supplementation of Ang II (1 mM) also increased ACE2 protein, and the latter failed to show significant change compared to pressurized control without Ang II. Ang II administration reduced ACE2 protein in the membranous fraction under pressurized condition. Administration of nifedipine (1 mM) protected cells from this ACE2 protein reduction at the HAEC membrane. Conclusions. These results indicate that pulsatile mechanical pressure and Ang II affect ACE2 in HAECs. Our findings suggest that blood pressure reduction with a calcium channel blocker is beneficial for the conservation of ACE2, and may provide a potential therapeutic target beyond blood pressure lowering in hypertensive patients. IntroductionRegulation of the renin-angiotensin system is a well-established strategy that has been used for the treatment of cardiovascular diseases during the past few decades. Two types of angiotensinconverting enzyme (ACE) have been noted, and the clinical importance of conventional ACE (i.e. not only the validity of its blood pressureregulating effect by the production of angiotensin II (Ang II), but also the benefits beyond blood pressure lowering provided by agents that inhibit ACE activity) has been reported.1,2 ACE2 is another type of ACE, and the findings of this molecule as an Ang II breakdown enzyme indicate that a new therapeutic strategy for blood pressure regulation may be developed. 3 The recent studies of ACEs indicated the mechanisms for the regulation of gene expression, 4 localization, 5 and the presence of homologues 6 as well as multiple transcripts. However, the physiological and pathological functions of local ACE2, especially in human endothelial cells, and the effect of Ang II and/or pressure stress have not been well characterized.Recently, we reported that a particular type of mechanical stress, a pulsatile atmospheric pressure produced by an original pure pressureloading apparatus, has a cell proliferating effect and modulates the activities of cell-surface ACE in human aortic smooth muscle cells. 8In the present study, we used this device to show the effect on the expression of ACE2 and the localization of ACE2 in human aortic endothelial cells (HAEC) when cells were exposed to pulsatile-mechanic...

show abstract

Pulsatile Mechanical Pressure Promotes Angiotensin-Converting Enzyme Expression in Aortic Smooth Muscle Cells

Cited by 17 publications

References 32 publications

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

Proteomic Analysis in Aortic Media of Patients With Marfan Syndrome Reveals Increased Activity of Calpain 2 in Aortic Aneurysms

<b>Docosahexaenoic acid suppresses angiotensin II-induced A7r5 vascular smooth muscle cell proliferation and migration under pulsatile pressure str</b><b>ess </b>

Angiotensin II reduces membranous angiotensin-converting enzyme 2 in pressurized human aortic endothelial cells

Contact Info

Product

Resources

About