Time course involvement of matrix metalloproteinases in the vascular alterations of renovascular hypertension

Ceron, Carla S.; Rizzi, Élen; Guimaraes, Danielle; Martins-Oliveira, Alisson; Cau, Stefany B.A.; Ramos, J. Galvão; Gerlach, Raquel Fernanda; Tanus‐Santos, José Eduardo

doi:10.1016/j.matbio.2012.01.009

Cited by 59 publications

(47 citation statements)

References 41 publications

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“…This study is the first report showing beneficial effects of PDTC on 2K1C hypertension-induced cardiac hypertrophy with the prevention of increases in MMP-2 activity. 2K1C hypertension is essentially dependent on renin-angiotensin system activation [21], which increases angiotensin II concentrations, thus allowing in vivo confirmation of the role of angiotensin II in NF-jB-induced MMP transcription demonstrated in cell culture [22]. Previous data confirm that the heart levels of angiotensin II and reactive oxygen species increased over time in the cardiovascular system of 2K1C hypertensive rats [21,23,24], suggesting continuous activation of pro-fibrotic pathways in this model.…”

Section: Discussionsupporting

confidence: 60%

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

Cau

Guimaraes

Rizzi

et al. 2015

Basic Clin Pharma Tox

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Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF-кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up-regulation. We suggested that treatment with PDTC could prevent 2-kidney, 1-clip (2K1C) hypertension-induced left ventricular remodelling. Sham-operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with haematoxylin/eosin sections, and fibrosis was quantified in picrosirius red-stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography, and cardiac MMP-2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricular and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP-2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP-2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMP expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension.It is well known that cardiac hypertrophy develops in response to many pathophysiological stimuli, particularly to pressure/volume overload and neurohormonal activation [1]. Although hypertension-associated cardiac remodelling is an initial adaptive process, sustained remodelling ultimately leads to progressive heart failure and death [1][2][3]. Common morphological features in hypertension-associated left ventricular remodelling include enlargement of cardiomyocytes and stimulated collagen turnover, resulting in net accumulation of interstitial collagen in cardiovascular tissues [3,4].Due to their fundamental role in extracellular matrix turnover and reorganization, matrix metalloproteinases (MMP), a so-called group of metalloenzymes, has been implicated as mediators of cardiac hypertrophy [5,6]. MMPs are proteases dependent on zinc and calcium and cleave several components of the extracellular matrix such as collagen, promoting the remodelling of tissue architecture and cell growth under both physiological and pathological conditions [7]. Additionally, MMP-2 degrades intracellular proteins such as troponin-I [8], myosin light chain [9], a-actinin [10] and titin [11], thus contributing to cardiac dysfunction. Transgenic mice with increased MMP-2 expression in cardiomyocytes deve...

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Section: Discussionsupporting

confidence: 60%

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

Cau

Guimaraes

Rizzi

et al. 2015

Basic Clin Pharma Tox

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“…Interestingly, we have previously shown that MMP-2 polymorphisms and haplotypes studied here modify MMP-2 and TIMP-2 concentrations in patients with pre-eclampsia [16] or with other disease conditions [28,29], and therefore, it is reasonable to hypothesize that these MMP-2 polymorphisms could affect the responses to antihypertensive therapy, at least in patients with pre-eclampsia. Indeed, imbalanced MMP-2 activity has been implicated in both functional [30] and structural [31][32][33] alterations of the cardiovascular system affecting the regulation of arterial blood pressure. Therefore, it is possible that higher circulating MMP-2 levels in hypertensive disorders of pregnancy contribute to the hypertension in these hypertensive disorders of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

Palei

Sandrim

Amaral

et al. 2012

Basic Clin Pharma Tox

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Imbalanced matrix metalloproteinase (MMP) expression, including MMP-2, has been demonstrated in pre-eclampsia. However, little is known about the effect of polymorphisms in MMP-2 gene on hypertensive disorders of pregnancy. We examined whether two functional MMP-2 polymorphisms (g.-1306C>T and g.-735C>T) are associated with pre-eclampsia and/or gestational hypertension and whether these polymorphisms affect therapeutic responses in women with these conditions. We studied 216 healthy pregnant women (HP), 185 patients with gestational hypertension (GH) and 216 patients with pre-eclampsia (PE). They were stratified as responsive or non-responsive to antihypertensive therapy according to clinical and laboratorial parameters of therapeutic responsiveness. Genomic DNA was extracted from whole blood and genotypes for g-1306C>T and g.-735C>T polymorphisms were determined by real-time PCR using Taqman allele discrimination assays. Haplotype frequencies were inferred using the PHASE 2.1 program. The distributions of MMP-2 genotypes and haplotypes were similar in HP, GH and PE patients (p > 0.05). In addition, we found no significant differences in MMP-2 genotype or haplotype frequencies when GH or PE patients were classified as responsive or non-responsive to antihypertensive therapy (p > 0.05). Our results suggest that MMP-2 polymorphisms do not affect the susceptibility to hypertensive disorders of pregnancy. In parallel, MMP-2 polymorphisms apparently do not affect the responsiveness to antihypertensive therapy of women with these hypertensive disorders of pregnancy.Pre-eclampsia is a fairly common clinical condition characterized by new-onset hypertension and proteinuria during pregnancy, probably as a result of inadequate trophoblast invasion of the maternal uterine spiral arteries and poor placental perfusion [1]. Reduced blood flow promotes placental release of vasopressors [2], oxidative stress and pro-inflammatory alterations leading to vascular dysfunction [3].Matrix metalloproteinases (MMPs) are a family of structurally related, zinc-dependent enzymes with multiple functions and tissue distribution. Their activity target extracellular matrix components during development and morphogenesis [4]. Specifically, MMP-2 is involved in remodelling of placental and uterine arteries [5,6], and abnormal MMP-2 expression has been reported in hypertensive disorders of pregnancy [7][8][9][10].Under normal circumstances, MMP-2 activity is regulated at the level of transcription, activation of latent forms and inhibition by endogenous MMP inhibitors (tissue inhibitors of metalloproteinase; TIMPs) [4]. In this respect, two functional MMP-2 genetic polymorphisms apparently affect MMP-2 transcriptional levels: the g.-1306C>T and the g.-735C>T. In vitro studies showed that the 'C' to 'T' substitutions at 1306 and 735 positions in promoter region of MMP-2 gene, respectively, result in increased MMP-2 transcription [11,12]. Interestingly, while both polymorphisms have been associated with hypertension-related complications...

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“…Hypertension appears to be one type of insult that enhances vascular connective tissue formation and induced an increased collagen synthesis and an increased total amount of collagen [61][62][63][64][65][66]. Wolinsky [61] studied the long-term effects of hypertension on the aortic wall of male Carworth rats.…”

Section: Hypertension and Aortic Collagenmentioning

confidence: 99%

“…The observed thickening and changes in elasticity of blood vessels in hypertension may be explained by the increased collagen biosynthesis. In the early phase of hypertension there are increased aortic collagen and elastin contents, which are associated with vascular hypertrophy [66]. Increased collagen biosynthesis may also be an early indicator of the vascular hypertension-induced lesions.…”

Section: Hypertension and Aortic Collagenmentioning

confidence: 99%

The Role of Collagen in the Aorta's Structure

Berillis¹

2013

TOCVJ

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Aorta is the largest artery in the body. Anatomically, it is traditionally divided into the ascending, the aortic arch, the descending, the thoracic and the abdominal aorta. Collagen is one of the most important components of the aortic wall. Its concentration and its total amount play a significant role in the aortas' function and mechanical properties, such as tensile strength and stiffness. The two main types of collagen found in the aorta are types I and III and they account for 80-90% of the total collagen. Age, sex hormones, aneurysms and hypertension are factors that can alter collagen and its subtypes in the aorta wall. As the aorta is a crucial artery and collagen is one of its most important components, collagen study is a helpful way to deal with aorta's abnormalities.

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Time course involvement of matrix metalloproteinases in the vascular alterations of renovascular hypertension

Cited by 59 publications

References 41 publications

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

The Role of Collagen in the Aorta's Structure

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