Roles of MicroRNA-122 in Cardiovascular Fibrosis and Related Diseases

Endothelial mesenchymal transition (EndMT) has been described as a fundamental process during embryogenesis; however, it can occur also in adult age, underlying pathological events, including fibrosis. Indeed, during EndMT, the endothelial cells lose their specific markers, such as vascular endothelial cadherin (VE-cadherin), and acquire a mesenchymal phenotype, expressing specific products, such as α-smooth muscle actin (α-SMA) and type I collagen; moreover, the integrity of the endothelium is disrupted, and cells show a migratory, invasive and proliferative phenotype. Several stimuli can trigger this transition, but transforming growth factor (TGF-β1) is considered the most relevant. EndMT can proceed in a canonical smad-dependent or non-canonical smad-independent manner and ultimately regulate gene expression of pro-fibrotic machinery. These events lead to endothelial dysfunction and atherosclerosis at the vascular level as well as myocardial hypertrophy and fibrosis. Indeed, EndMT is the mechanism which promotes the progression of cardiovascular disorders following hypertension, diabetes, heart failure and also ageing. In this scenario, hydrogen sulfide (H2S) has been widely described for its preventive properties, but its role in EndMT is poorly investigated. This review is focused on the evaluation of the putative role of H2S in the EndMT process.

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Abstract MP13: TRPM7 Downregulation Contributes To Cardiovascular Injury And Hypertension Induced By Aldosterone And Salt

Hypertension ◽

10.1161/hyp.76.suppl_1.mp13 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Francisco J Rios ◽

ZhiGuo Zou ◽

Karla B Neves ◽

Sarah S Nichol ◽

Livia L Camargo ◽

...

Keyword(s):

Molecular Mechanisms ◽

Cardiac Fibroblasts ◽

Protective Role ◽

Internal Diameter ◽

Resistance Arteries ◽

Cross Sectional ◽

Vessel Structure ◽

Cardiovascular Fibrosis ◽

Fold Activation

TRPM7 has cation channel and kinase properties, is permeable to Mg 2+ , Ca 2+ , and Zn 2+ and is protective in the cardiovascular system. Hyperaldosteronism, which induces hypertension and cardiovascular fibrosis, is associated with Mg 2+ wasting. Here we questioned whether TRPM7 plays a role in aldosterone- induced hypertension and fibrosis and whether it influences cation regulation. Wild-type (WT) and TRPM7-deficient (M7+/Δ) mice were treated with aldosterone (600μg/Kg/day) and/or 1% NaCl (drinking water) (aldo, salt or aldo-salt) for 4 weeks. Blood pressure (BP) was evaluated by tail-cuff. Vessel structure was assessed by pressure myography. Molecular mechanisms were investigated in cardiac fibroblasts (CF) from WT and M7+/Δ mice. Protein expression was assessed by western-blot and histology. M7+/Δ mice exhibited reduced TRPM7 expression (30%) and phosphorylation (62%), levels that were recapitulated in WT aldo-salt mice. M7+/Δ exhibited increased BP by aldo, salt and aldo-salt (135-140mmHg) vs M7+/Δ-veh (117mmHg) (p<0.05), whereas in WT, BP was increased only by aldo-salt (134mmHg). Mesenteric resistance arteries from WT aldo-salt exhibited increased wall/lumen ratio (80%) and reduced internal diameter (15%) whereas vessels from M7+/Δ exhibited thinner walls by reducing cross-sectional area (35%) and increased internal diameter (23%) after aldo-salt. Aldo-salt induced greater collagen deposition in hearts (68%), kidneys (126%) and aortas (45%) from M7+/Δ vs WT. Hearts from M7+/Δ veh exhibited increased TGFβ, IL-11 and IL-6 (1.9-fold), p-Smad3 and p-Stat1 (1.5-fold) whereas in WT these effects were only found after aldo-salt. Cardiac expression of protein phosphatase magnesium-dependent 1A (PPM1A), a Mg 2+ -dependent phosphatase, was reduced (3-fold) only in M7+/Δ mice. M7+/Δ CF showed reduced proliferation (30%) and PPM1A (4-fold) and increased expression of TGFβ, IL-11 and IL-6 (2-3-fold), activation of Stat1 (2-fold), Smad3 (9-fold) and ERK1/2 (8-fold) compared with WT. Mg 2+ supplementation normalized cell proliferation and reduced protein phosphorylation in M7+/Δ CF (p<0.05). Our findings indicate a protective role of TRPM7 in aldosterone-salt induced cardiovascular injury through Mg 2+ -dependent mechanisms.

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Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases plasminogen activator inhibitor type-1 production

Journal of Hypertension ◽

10.1097/hjh.0b013e32834347de ◽

2011 ◽

Vol 29 (4) ◽

pp. 724-731 ◽

Cited By ~ 53

Author(s):

Khandaker Siddiquee ◽

Jessica Hampton ◽

Susan Khan ◽

Dan Zadory ◽

Linda Gleaves ◽

...

Keyword(s):

Angiotensin Ii ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor Type ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Cardiovascular Fibrosis ◽

Activator Inhibitor

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The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

Antioxidants ◽

10.3390/antiox10081274 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1274

Author(s):

Francisco V. Souza-Neto ◽

Sara Jiménez-González ◽

Beatriz Delgado-Valero ◽

Raquel Jurado-López ◽

Marie Genty ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Control Diet ◽

Ang Ii ◽

Mitochondrial Oxidative Stress ◽

Relevant Role ◽

Male Wistar Rats ◽

Cardiovascular Fibrosis ◽

Stress Activation

We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP; 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6; 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP; 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p < 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10−6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role.

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Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice

Journal of Clinical Investigation ◽

10.1172/jci28764 ◽

2007 ◽

Vol 117 (7) ◽

pp. 1914-1925 ◽

Cited By ~ 59

Author(s):

Sandrine Billet ◽

Sabine Bardin ◽

Sonia Verp ◽

Véronique Baudrie ◽

Annie Michaud ◽

...

Keyword(s):

Angiotensin Ii ◽

Receptor Type ◽

Angiotensin Ii Receptor ◽

Gain Of Function ◽

Cardiovascular Fibrosis

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Cardiovascular ultrashort echo time to map fibrosis—promises and challenges

British Journal of Radiology ◽

10.1259/bjr.20190465 ◽

2019 ◽

Vol 92 (1103) ◽

pp. 20190465

Author(s):

Joanne D Schuijf ◽

Bharath Ambale-Venkatesh ◽

Yoshimori Kassai ◽

Yoko Kato ◽

Larry Kasuboski ◽

...

Keyword(s):

Cardiac Fibrosis ◽

Extracellular Volume ◽

Volume Determination ◽

Ultrashort Echo Time ◽

Cardiac Devices ◽

Potential Applications ◽

Patients At Risk ◽

Echo Time ◽

Cardiovascular Fibrosis

Increased collagen, or fibrosis, is an important marker of disease and may improve identification of patients at risk. In addition, fibrosis imaging may play an increasing role in guiding therapy and monitoring its effectiveness. MRI is the most frequently used modality to detect, visualize and quantify fibrosis non-invasively. However, standard MRI techniques used to phenotype cardiac fibrosis such as delayed enhancement and extracellular volume determination by T1 mapping, require the administration of gadolinium-based contrast and are particularly difficult to use in patients with cardiac devices such as pacemakers and automatic defibrillators. Therefore, such methods are limited in the serial evaluation of cardiovascular fibrosis as part of chronic disease monitoring. A method to directly measure collagen amount could be of great clinical benefit. In the current review we will discuss the potential of a novel MR technique, ultrashort echo time (UTE) MR, for fibrosis imaging. Although UTE imaging is successfully applied in other body areas such as musculoskeletal applications, there is very limited experience so far in the heart. We will review the established methods and currently available literature, discuss the technical considerations and challenges, show preliminary in vivo images and provide a future outlook on potential applications of cardiovascular UTE.

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