Angiotensin II Type 2 Receptor Mediates Vascular Smooth Muscle Cell Apoptosis in Cystic Medial Degeneration Associated With Marfan’s Syndrome

Nagashima, Hirotaka; Sakomura, Yasunari; Aoka, Yoshikazu; Uto, Kenta; Kameyama, Kin-ichi; Ogawa, Motoko; Aomi, Shigeyuki; Koyanagi, Hitoshi; Ishizuka, Naoko; Naruse, Mitsuhide; Kawana, Masatoshi; Kasanuki, Hiroshi

doi:10.1161/hc37t1.094856

Cited by 89 publications

(69 citation statements)

References 17 publications

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“…Similar observations have been made in normotensive Sprague-Dawley rats, leading to speculation that the activation of both AT 1 and AT 2 receptors is necessary for the trophic and proliferative effects of ANG II (2). However, no consensus has been reached on the biological consequence of AT 2 receptor activation because of the contradictory effects observed in other cell types, such as ANG II-mediated apoptosis and growth inhibition (15). The lack of consistency in published reports comparing the biological functions of the ANG II receptor subtypes may be attributed to differences in the experimental systems that have been employed.…”

mentioning

confidence: 61%

Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Louis

Saward

Zahradka

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Louis S, Saward L, Zahradka P. Both AT1 and AT2 receptors mediate proliferation and migration of porcine vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 301: H746 -H756, 2011. First published May 27, 2011 doi:10.1152/ajpheart.00431.2010.-Angiotensin receptor antagonists have shown clinical promise in modulating vascular disease, in part by limiting smooth muscle cell proliferation and migration. The majority of studies examining the contribution of these receptors have been undertaken in cells derived from rat aorta, which primarily express the ANG II type 1 (AT1) receptor. This investigation studied the relative contribution of AT1 and ANG II type 2 (AT2) receptors to the mitogenic program of porcine smooth muscle cells. Smooth muscle cells were derived from porcine coronary artery explants. The presence of both AT1 and AT2 receptors was demonstrated through ligand binding and RT-PCR analysis. Biochemical and cellular markers of proliferation were monitored in the presence of selective receptor antagonists. Smooth muscle cell migration was measured using both wound healing and Boyden chamber migration assays. Visualization of the AT1 and AT2 receptors in growing and quiescent porcine smooth muscle cells with epifluorescence microscopy demonstrated that their subcellular distribution varied with growth state. An examination with several growth assays revealed that both AT1-specific losartan and AT2-specific PD-123319 receptor antagonists inhibited ANG II-stimulated RNA and DNA synthesis, PCNA expression, and hyperplasia. ANG II induced both directional and nondirectional cell migration. AT1 receptor antagonist treatment significantly decreased ANG II-induced directional migration only, whereas AT2 receptor antagonist treatment significantly reduced both modes of migration. Interestingly, the focal adhesion kinase inhibitor PF-573228 also blocked migration but not proliferation. Furthermore, focal adhesion kinase activation in response to ANG II was prevented only by PD-123319, indicating that this activation is downstream of the AT2 receptor. The observed role of the AT2 receptor in ANG II-induced migration was confirmed with smooth muscle cells depleted of the AT2 receptor with short hairpin RNA treatment.focal adhesion kinase; angiotensin II types 1 and 2 receptors; losartan; PD-123319; PF-573228 EXCESSIVE SMOOTH MUSCLE CELL (SMC) growth has been implicated in the development and progression of cardiovascular diseases such as atherosclerosis and hypertension. A critical mediator of these disease processes is angiotensin II (ANG II), a biologically active peptide with a broad range of physiological effects on the cardiovascular system (8). The actions of ANG II are mediated by at least two different ANG II receptors, ANG II types 1 (AT 1 ) and 2 (AT 2 ) receptors; however, the AT 1 receptor is typically regarded as the primary mediator of the vascular response to ANG II. As a consequence, many studies of SMCs have not included an analysis of the AT 2 receptor and fewer details of its biological f...

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confidence: 61%

Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Louis

Saward

Zahradka

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Some patients may not tolerate b-blockers, and alternative drugs which reduce the ejection impulse such as calcium antagonists, 33 and angiotensin converting enzyme (ACE) inhibitors have been considered. ACE inhibitors also reduce vascular smooth muscle cell apoptosis in vitro through an angiotensin II type 2 (AT2) receptor-dependent mechanism (apoptosis is implicated in the cystic medial degeneration seen in the Marfan aorta 34 ). This theoretical benefit may be in addition to any haemodynamic effects.…”

Section: Cardiovascular System In Marfan Syndromementioning

confidence: 99%

Marfan syndrome: clinical diagnosis and management

2007

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In association withMarfan syndrome: clinical diagnosis and management Marfan syndrome is a multisystem connective tissue disorder usually associated with mutation in fibrillin, and occasionally with mutation in TGFBR1 or 2. The clinical diagnosis is made using the Ghent nosology, which will unequivocally diagnose or exclude Marfan syndrome in 86% of cases. Use of a care pathway can help implementation of the nosology in the clinic. The penetrance of some features is age dependent, so the nosology must be used with caution in children. Molecular testing may be helpful in this context. The nosology cannot be used in families with isolated aortic dissection, or with related conditions such as Loeys -Dietz syndrome, although it may help identify families for further diagnostic evaluation because they do not fulfill the nosology, despite a history of aneurysm. Prophylactic medical (eg b-blockade) and surgical intervention is important in reducing the cardiovascular complications of Marfan syndrome. Musculoskeletal symptoms are common, although the pathophysiology is less clear -for example, the correlation between dural ectasia and back pain is uncertain. Symptoms in other systems require specialist review such as ophthalmology assessment of refractive errors and ectopia lentis. Pregnancy is a time of increased cardiovascular risk for women with Marfan syndrome, particularly if the aortic root exceeds 4 cm at the start of pregnancy. High-intensity static exercise should be discouraged although low-moderate intensity dynamic exercise may be beneficial. The diagnosis and management of Marfan syndrome requires a multidisciplinary team approach, in view of its multisystem effects and phenotypic variability.

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“…For example, apoptosis induced by Ang II could be completely prevented by Ang II neutralizing antibodies or by an Ang II receptor antagonist (31). ACE plays a role in apoptosis in a wide variety of tissues, including neural tissues, vascular endothelium, smooth muscle, and fetal adrenals (21,(37)(38)(39). Interestingly, ACE and Ang II have also been linked to upregulation of TNF-α (40).…”

Section: Introductionmentioning

confidence: 99%

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

et al. 2007

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Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-α). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-α expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-α, Bcl-2, and Bax expression. TNF-α mRNA was significantly lower with ACE-I treatment compared to placebo at every time point; as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

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Angiotensin II Type 2 Receptor Mediates Vascular Smooth Muscle Cell Apoptosis in Cystic Medial Degeneration Associated With Marfan’s Syndrome

Cited by 89 publications

References 17 publications

Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Marfan syndrome: clinical diagnosis and management

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

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Angiotensin II Type 2 Receptor Mediates Vascular Smooth Muscle Cell Apoptosis in Cystic Medial Degeneration Associated With Marfan’s Syndrome

Cited by 89 publications

References 17 publications

Both AT1and AT2receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Both AT1and AT2receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Marfan syndrome: clinical diagnosis and management

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

Contact Info

Product

Resources

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Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells

Both AT₁and AT₂receptors mediate proliferation and migration of porcine vascular smooth muscle cells