Early Increased MT1-MMP Expression and Late MMP-2 and MMP-9 Activity during Angiotensin II Induced Aneurysm Formation

Eagleton, Matthew J.; Ballard, Nicole E.; Lynch, Erin M.; Srivastava, Sunita D.; Upchurch, Gilbert R.; Stanley, James C.

doi:10.1016/j.jss.2006.03.026

Cited by 65 publications

(54 citation statements)

References 38 publications

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“…These factors include angiotensin II, angiotensin-converting enzyme (ACE) and transforming growth factor-beta. In animal models, angiotensin II infusion leads to increased matrix metalloproteinase activity in the vasculature, resulting in vascular smooth muscle cell apoptosis and aneurysm formation (15). In addition, higher ACE levels occurring in the setting of an ACE gene variant (DD genotype polymorphism) are associated with a greater propensity for aortic aneurysm (16).…”

Section: Discussionmentioning

confidence: 99%

The prevalence and clinical impact of obesity in adults with Marfan syndrome

Yetman

McCrindle

2010

Canadian Journal of Cardiology

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Despite improvement in survival noted throughout the past few decades (1), patients with Marfan syndrome remain at risk for premature death secondary to the cardiovascular complications of aortic dilation and dissection (2). Risk factors for such complications remain poorly defined, thereby impeding attempts at risk stratification for the individual patient. Family history of aortic dissection (3) and spontaneous genetic mutations (4) have been identified as risk factors but, currently, no potentially modifiable risk factors have been elucidated.The underlying biomechanical abnormalities in Marfan syndrome have been well described. Patients with Marfan syndrome have reduced aortic distensibility, which becomes progressively more abnormal with increasing age (5). These biomechanical abnormalities precede the vascular complication of aortic dilation and dissection, and may reflect both endothelial and vascular smooth muscle cell abnormalities of the aortic wall (6-8).The current obesity epidemic has been the subject of much lay and scientific attention. Obesity, hyperlipidemia, smoking and hypertension have been established as clear risk factors for atherosclerotic arterial disease (9). These risk factors predispose to impaired vascular endothelial function, thereby increasing the risk of vascular complications including coronary arterial obstructive disease and stroke (10). Marfan syndrome is characteristically associated with an asthenic body habitus; as a result, these patients have been considered to be exempt from the current obesity epidemic.We sought to determine the prevalence of obesity and overweight in an adult cohort of patients with Marfan syndrome, to assess the prevalence of other cardiovascular risk factors among this patient group -namely smoking, hyperlipidemia, diabetes and hypertensionand to determine what, if any, clinical impact such risk factors had on outcome in this patient cohort. BACKGROUND:Patients with Marfan syndrome characteristically have an asthenic body habitus and are considered to be exempt from the obesity epidemic. OBJECTIVE: To examine the prevalence and clinical impact of obesity in a cohort of adults with Marfan syndrome. METHODS: Fifty outpatients (30 female) with a mean (± SD) age of 38±13 years were studied. Demographic variables including previously identified risk factors for aortic dissection were recorded. Body mass index (BMI) was determined and patients were classified as normal (BMI less than 25 kg/m 2 ), overweight (BMI 25 kg/m 2 to 29.9 kg/m 2 ) or obese (BMI 30 kg/m 2 or greater). Other cardiovascular risk factors were examined. An adverse clinical outcome was defined as either the attainment of surgical criteria for aortic root replacement or the presence of aortic dissection. RESULTS: A family history of aortic dissection was present in 13 (26%) patients. In 23 (46%) patients, there was no known family history of Marfan syndrome. Mean BMI was 25.4±7.4 kg/m 2 , with 18 (36%) patients having an elevated BMI. Positive smoking status was present in 15 (30%), hyp...

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Section: Discussionmentioning

confidence: 99%

The prevalence and clinical impact of obesity in adults with Marfan syndrome

Yetman

McCrindle

2010

Canadian Journal of Cardiology

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“…3C) in the activity of this enzyme, among other factors, are involved and believed to be crucial in the early stages of AMD (19,46,78). ANG II has been shown to regulate MMP-2 in nonocular tissues (20,24,33,73). We decided to analyze whether ANG II might alter MMP-2 activity and protein expression in RPE cells.…”

Section: Human Rpe Expresses Both Ang II Receptor Subtypesmentioning

confidence: 99%

“…On the other hand, the signaling mechanisms of the AT2 receptor are diverse, and only a few of them have been characterized (17). Although ANG II receptor expression has been confirmed in the retinal vasculature (22, 63), retina (5, 62, 75), and the pigment epithelium-choroid complex (65,67), nothing is known about the regulation of ANG II receptor subtype expression and their function in the RPE, which is a cell type of pivotal importance in the progression of AMD (25).Among its many actions, ANG II promotes interstitial extracellular matrix (ECM) turnover by regulation of the ECM proteins (12,20,33,66,70,73,74,77). For example, ANG II has been shown to stimulate synthesis of fibronectin, collagen, tissue inhibitor of metalloproteinase (TIMP)-2, and matrix metalloproteinase (MMP)-2 in mesangial and proximal tubule cells through activation of transforming growth factor-␤ secretion (62,27).…”

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confidence: 99%

“…Among its many actions, ANG II promotes interstitial extracellular matrix (ECM) turnover by regulation of the ECM proteins (12,20,33,66,70,73,74,77). For example, ANG II has been shown to stimulate synthesis of fibronectin, collagen, tissue inhibitor of metalloproteinase (TIMP)-2, and matrix metalloproteinase (MMP)-2 in mesangial and proximal tubule cells through activation of transforming growth factor-␤ secretion (62,27).…”

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confidence: 99%

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Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II

Striker

Praddaude

Garnica

et al. 2008

American Journal of Physiology-Cell Physiology

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Striker GE, Praddaude F, Alcazar O, Cousins SW, MarinCastañ o ME. Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II. Am J Physiol Cell Physiol 295: C1633-C1646, 2008. First published October 15, 2008 doi:10.1152/ajpcell.00092.2008.-The early stage of age-related macular degeneration (AMD) is characterized by the formation of subretinal pigment epithelium (RPE) deposits as a result of the dysregulation in the turnover of extracellular matrix (ECM) molecules. However, the mechanism involved remains unclear. Hypertension (HTN) is an important risk factor for AMD, and angiotensin II (ANG II) is the most important hormone associated with HTN. However, the relevance of ANG II receptors and ANG II effects on RPE have not been investigated yet. Therefore, the expression and regulation of ANG II receptors as well as the ECM turnover were studied in human RPE. ANG II receptors were expressed and upregulated by ANG II in human RPE. This regulation resulted in functional receptor expression, since an increase in intracellular concentration of calcium was observed upon ANG II stimulation. ANG II also increased matrix metalloproteinase (MMP)-2 activity and MMP-14 at the mRNA and protein levels as well as type IV collagen degradation. These ANG II effects were abolished in the presence of the ANG II receptor subtype 1 (AT1) receptor antagonist candesartan. In contrast, ANG II decreased type IV collagen via both AT1 and AT2 receptors, suggesting a synergistic effect of the two receptor subtypes. In conclusion, we have confirmed the presence of ANG II receptors in human RPE and their regulation by ANG II as well as the regulation of ECM molecules via ANG II receptors. Our data support the hypothesis that ANG II may exert biological function in RPE through ANG II receptors and that ANG II may cause dysregulation of molecules that play a major role in the turnover of ECM in RPE basement membrane and Bruch's membrane, suggesting a pathogenic mechanism to explain the link between HTN and AMD. calcium; hypertension; Bruch's membrane EARLY AGE-RELATED MACULAR DEGENERATION (AMD) is one of the most common irreversible causes of severe loss of vision in elderly population (23,39). Dysfunction of retinal photoreceptors is the ultimate cause of vision loss. However, the initial pathogenic target of AMD is the retinal pigment epithelium (RPE) and the subjacent extracellular matrix (Bruch's membrane, or BrM) (25). Although age is the major determinant for developing AMD, clinical studies have revealed a number of systemic and environmental risk factors (23,49,54). Among them, hypertension (HTN) is of special relevance (29,34,37,39). However, the mechanism(s) by which HTN may affect AMD remains unclear. Interestingly, different reports have related that angiotensin II (ANG II), the final product of the renin-angiotensin system (RAS) and the most important hormone associated with HTN, may contribute to chronic diseases (17,43,58,69).Expression and localization ...

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“…Ang II also intensifies dissecting AAA evolution in mice by stimulating the production and activity of MMPs with consequent degradation of the arterial wall integrity [47,48]. Indeed, doxycycline, a broad specificity inhibitor of MMPs, attenuates the incidence and severity of dissecting AAA induced by Ang II infusion [49].…”

Section: Renin Angiotensin System -Classical Systemmentioning

confidence: 99%

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

Fraga‐Silva

Trachet²,

Stergiopulos³

2015

CPD

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Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1β inhibition, anti-angiogenic agents and urocortins.

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Early Increased MT1-MMP Expression and Late MMP-2 and MMP-9 Activity during Angiotensin II Induced Aneurysm Formation

Cited by 65 publications

References 38 publications

The prevalence and clinical impact of obesity in adults with Marfan syndrome

The prevalence and clinical impact of obesity in adults with Marfan syndrome

Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

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