Doxycycline Prevents Acute Pulmonary Embolism-Induced Mortality and Right Ventricular Deformation in Rats

Cáu, Stêfany Bruno de Assis; Barato, Renan C.; Celes, Mara Rúbia Nunes; Muniz, Jaqueline Jóice; Rossi, Marcos A.; Tanus‐Santos, José Eduardo

doi:10.1007/s10557-013-6458-9

Cited by 19 publications

(24 citation statements)

References 31 publications

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“…In fact, cTnI release may be explained by APT‐induced cardiomyocyte damage and serum cTnI concentrations increase in proportion to the degree of APT severity . Importantly, we found that doxycycline prevented RVD and dilatation, probably as result of protection against cardiomyocyte injury (revealed by serum cTnI concentrations) . These beneficial effects could be of great clinical relevance to patients at high risk who present RVD after APT.…”

Section: Discussionmentioning

confidence: 58%

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

Neto-Neves

Sousa-Santos

Ferraz

et al. 2013

J Cellular Molecular Medi

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Activated matrix metalloproteinases (MMPs) cause cardiomyocyte injury during acute pulmonary thromboembolism (APT). However, the functional consequences of this alteration are not known. We examined whether doxycycline (a MMP inhibitor) improves right ventricle function and the cardiac responses to dobutamine during APT. APT was induced with autologous blood clots (350 mg/kg) in anaesthetized male lambs pre-treated with doxycycline (Doxy, 10 mg/kg/day, intravenously) or saline. Non-embolized control lambs received doxycycline pre-treatment or saline. The responses to intravenous dobutamine (Dob, 1, 5, 10 μg/kg/min.) or saline infusions at 30 and 120 min. after APT induction were evaluated by echocardiography. APT increased mean pulmonary artery pressure and pulmonary vascular resistance index by ∼185%. Doxycycline partially prevented APT-induced pulmonary hypertension (P < 0.05). RV diameter increased in the APT group (from 10.7 ± 0.8 to 18.3 ± 1.6 mm, P < 0.05), but not in the Doxy+APT group (from 13.3 ± 0.9 to 14.4 ± 1.0 mm, P > 0.05). RV dysfunction on stress echocardiography was observed in embolized lambs (APT+Dob group) but not in embolized animals pre-treated with doxycycline (Doxy+APT+Dob). APT increased MMP-9 activity, oxidative stress and gelatinolytic activity in the RV. Although doxycycline had no effects on RV MMP-9 activity, it prevented the increases in RV oxidative stress and gelatinolytic activity (P < 0.05). APT increased serum cardiac troponin I concentrations (P < 0.05), doxycycline partially prevented this alteration (P < 0.05). We found evidence to support that doxycycline prevents RV dysfunction and improves the cardiac responses to dobutamine during APT.

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Section: Discussionmentioning

confidence: 58%

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

Neto-Neves

Sousa-Santos

Ferraz

et al. 2013

J Cellular Molecular Medi

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“…Increased cardiac MMP-2 expression in 2K1C hypertensive rats confers a more proteolytic profile that may account for increased collagen synthesis and breakdown. While increased proteolytic activity may contribute to degradation of myofilaments in acute cardiac conditions [35][36][37], chronic increases in this activity are associated with enhanced extracellular matrix deposition. This leads to hypertrophy likely because excessive MMP-2 activates pro-fibrotic intracellular pathways that increase collagen-I synthesis by cardiac fibroblasts [38].…”

Section: Discussionmentioning

confidence: 99%

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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“…In previous studies, MMP-9 and PAI-1 levels have been shown to be beneficial for the diagnosis of suspected pulmonary embolism [ 17 ]. In addition, the increased MMP levels have been shown to be associated with lung tissue damage and it was shown that MMP inhibition with doxycycline protects against acute pulmonary embolism-induced mortality and RV enlargement [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

The Diagnostic Role of Adiponectin in Pulmonary Embolism

Gül

Yıldırım

et al. 2016

BioMed Research International

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Background and Aims. Pulmonary thromboembolism (PTE) is a frequent disease with difficult diagnosis and high mortality. Misdiagnosis occurs in 2/3 patients and mortality rates reach up to 30%. The aim of our study was to investigate the role of adiponectin used in emergency service in diagnosis of PTE. Materials and Methods. 95 patients with suspected PTE included in the study. Plasma adiponectin and D-dimer levels were measured and chest X-ray and multidetector row computed tomography scan obtained. Diagnosis was supported by vascular filling defect on tomography. Control group consisted of patients with suspected PTE and normal chest computed tomography findings. Results. Mean D-dimer level was 4241.66 ± 1082.98 ng/mL in patients and 2211.21 ± 1765.53 ng/mL in the control group (p ≤ 0.05). Mean adiponectin level was 5.46 ± 4.39 μg/mL in patients and 7.68 ± 4.67 μg/mL in the control group (p ≤ 0.05). Wells and Geneva scores were higher in patients compared to the control group. Conclusions. As a result, we conclude that lower adiponectin levels have an important role in the diagnosis of PTE.

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Doxycycline Prevents Acute Pulmonary Embolism-Induced Mortality and Right Ventricular Deformation in Rats

Cited by 19 publications

References 31 publications

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism

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

The Diagnostic Role of Adiponectin in Pulmonary Embolism

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