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Introduction
Publications
Publications (74)
Abdominal aortic aneurysm (AAA) is a prevalent degenerative disease characterized by an exacerbated inflammation and destructive vascular remodeling. Unfortunately, effective pharmacological tools for the treatment of this disease remain a challenge. ATP-citrate lyase (ACLY), the primary enzyme responsible for acetyl-CoA biosynthesis, is a key regu...
Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatenin...
Background and Purpose
Mitochondrial dysfunction and inflammation contribute to a myriad of cardiovascular diseases. Deleterious crosstalk of mitochondria and persistent endoplasmic reticulum (ER) stress triggers oxidative stress, which is involved in the development of vascular diseases. This study determined if inhibition of mitochondrial stress...
Background and purpose: Persistent endoplasmic reticulum (ER) stress and its deleterious crosstalk with mitochondria trigger oxidative stress, mitochondrial dysfunction and inflammation contributing to the pathophysiology of a myriad of cardiovascular diseases linked with hypertension such as abdominal aortic aneurysm (AAA) and cardiac hypertrophy....
Abdominal aortic aneurysm (AAA) is increasing due to aging of the population and is a major cause of death among the elderly. Ultrasound screening programs are useful in early diagnosis, but aneurysm size is not always a good predictor of rupture. Our aim was to analyze the value of circulating molecules related to oxidative stress and inflammation...
Objective
Abdominal aortic aneurysm (AAA) is increasing due to aging of the population and is a major cause of death among the elderly. Ultrasound screening programs are useful in early diagnosis but aneurysm size is not always a good predictor of rupture. Thus, there is an urgent need to find new potential prognostic factors. Our aim is to determi...
Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy f...
Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examine...
Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification but the precise mechanisms are not fully elucidated. Our aim was to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We exami...
Hypertensive cardiac hypertrophy (HCH) is a common cause of heart failure, a major public health problem worldwide. However, the molecular bases of HCH have not been completely elucidated. Neuron-derived orphan receptor-1 (NOR-1) is a nuclear receptor whose role in cardiac remodelling is poorly understood. The aim of this study was to generate a tr...
Abdominal aortic aneurysm (AAA) is a vascular pathology with a high rate of morbidity and mortality and a prevalence that, in men over 65 years, can reach around 8%. In this disease, usually asymptomatic, there is a progressive dilatation of the vascular wall that can lead to its rupture, a fatal phenomenon in more than 80% of cases. The treatment...
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease with a complex aetiology that remains to be fully elucidated. Clinical management of AAA is limited to surgical repair, while an effective pharmacotherapy is still awaited. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have been involved in the pathogenesis of card...
Resumen
El aneurisma de aorta abdominal (AAA) es una patología vascular con una elevada tasa de morbimortalidad y una prevalencia que, en varones de más de 65 años, puede alcanzar el 8%. En esta enfermedad, habitualmente asintomática, se produce una dilatación progresiva de la pared vascular que puede llevar a su rotura, un fenómeno mortal en más d...
Prostanoids modulate the pathogenesis of vascular diseases such as atherosclerosis, in which inflammation has an important role. It is well known that inducible Ciclooxygenase-2 (COX-2) is responsible for prostanoid production associated with inflammation. Angiotensin II may be implicated through the expression of COX-2 in the vascular wall. The pu...
Lysyl oxidase (LOX) plays a critical role in extracellular matrix maturation and limits VSMC proliferation and vascular remodeling. We have investigated whether this anti-proliferative effect relies on the extracellular catalytically active LOX or on its biologically active propeptide (LOX-PP). High expression levels of both LOX and LOX-PP were det...
Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy...
INTRODUCTION
Fibulin-5 (FBLN5) is an elastogenic protein critically involved in extracellular matrix (ECM) remodelling, a key process in abdominal aortic aneurysm (AAA). However, the possible contribution of FBLN5 to AAA development has not been addressed.
METHODS
Expression levels were determined by real-time PCR and Western blot in human abdomin...
Vascular cell survival is compromised under pathological conditions such as abdominal aortic aneurysm (AAA). We have previously shown that the nuclear receptor NOR-1 is involved in the survival response of vascular cells to hypoxia. Here, we identify the anti-apoptotic protein cIAP2 as a downstream effector of NOR-1. NOR-1 and cIAP2 were up-regulat...
Aims:
Destructive remodelling of extracellular matrix (ECM) and inflammation lead to dilation and ultimately abdominal aortic aneurysm (AAA). Fibulin-5 (FBLN5) mediates cell-ECM interactions and elastic fibre assembly and is critical for ECM remodelling. We aimed to characterise FBLN5 regulation in human AAA and analyse the underlying mechanisms....
Clinical management of abdominal aortic aneurysms (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDACs expression in human AAA and to evaluate t...
Lysyl oxidase (LOX) is an extracellular matrix (ECM)-modifying enzyme that has been involved in cardiovascular remodeling. We explore the impact of LOX inhibition in ECM alterations induced by obesity in the cardiovascular system. LOX is overexpressed in the heart and aorta from rats fed a high-fat diet (HFD). β-Aminopropionitrile (BAPN), an inhibi...
Extracellular matrix (ECM) remodeling of the adipose tissue plays a pivotal role in the pathophysiology of obesity. The lysyl oxidase (LOX) family of amine oxidases, including LOX and LOX-like (LOXL) isoenzymes, controls ECM maturation, and up-regulation of LOX activity is essential in fibrosis; however, its involvement in adipose tissue dysfunctio...
Objective: Lysyl oxidase (LOX) is a key enzyme in extracellular matrix (ECM) remodelling. Because LOX deficiency is lethal, we have developed a transgenic mouse model to study the impact of LOX overexpression on cardiovascular remodelling. Design and method: A new mouse model that over-expresses human LOX was generated by conventional methods. Tran...
We previously reported that enhanced nuclear factor kappa B (NFκB) activity is responsible for resistance arteries dysfunction in type 2 diabetic mice.
In this study we aimed to determine whether augmented NFkB activity also impairs conductance artery (thoracic aorta) function in type 2 diabetic mice. We treated type 2 diabetic (db(-) /db(-) ) and...
Purpose: Lysyl oxidase (LOX) is an extracellular matrix-modifying enzyme that could play a critical role in vascular remodelling. We have developed a transgenic mouse model that over-expresses LOX in vascular smooth muscle cells (VSMC) to clarify whether LOX could regulate VSMC phenotype and vascular remodelling.
Methods: We designed a construct in...
Purpose: We have previously reported that leptin can participate in the cardiovascular fibrosis associated with obesity. One of the key steps in the synthesis and maturation of the ECM involves the enzyme lysyl oxidase (LOX), which allows the crosslinking of collagen and elastin fibers and the formation of a stable and insoluble ECM. Therefore, we...
Lysyl oxidase (LOX) is an extracellular matrix-modifying enzyme that seems to play a critical role in vascular remodelling. However, the lack of viable LOX-deficient animal models has been an obstacle to deep in LOX biology. In this study we have developed a transgenic mouse model that over-expresses LOX in vascular smooth muscle cells (VSMC) to cl...
We recently reported that ER stress plays a key role in vascular endothelial dysfunction during hypertension. In this study we aimed to elucidate the mechanisms by which ER stress induction and oxidative stress impair vascular endothelial function.
we conducted in vitro studies with primary endothelial cells from coronary arteries stimulated with t...
Type 2 diabetes (T2D) is associated with vascular complication. We hypothesized that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22(phox) expression impairs vascular endothelium-dependent relaxation in T2D. Type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice were treated with reactive oxygen species (ROS)...
Abdominal aorta aneurysm (AAA) is a major cause of mortality in men. The role of endoplasmic reticulum (ER) stress in the pathogenesis of AAA is unknown. Human AAA specimens from diabetic patients were found to have increased expression of ER stress markers. The inhibition of ER stress signaling with (taurine-conjugated ursodeoxycholic acid, Tudca)...
Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl2 affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteri...
Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor kappa B (NFκB) signaling contributes to vascular dysfunction in T2D. We have treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NFκB inhibitors (DHMEQ, 6mg/kg, twice a week and IKK-NBD peptide, 500 μg/kg/day) for f...
Background and purpose:
Regular physical activity is an effective non-pharmacological therapy for prevention and control of hypertension. We investigated the effects of aerobic exercise training in vascular remodelling and in the mechanical and functional alterations of coronary and small mesenteric arteries from spontaneously hypertensive rats (S...
Cardiovascular diseases are associated with the induction of endoplasmic reticulum (ER) stress. The induction of ER stress in C57BL/6J and p47phox-/- mice, by the injection of tunicamycin, greatly impaired vascular endothelium-dependent relaxation in C57BL/6J than in p47phox-/- mice. To determine the mechanism by which ER stress impairs endothelium...
Rationale and Objective: Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor kappa B (NFκB) signaling contributes to vascular dysfunction in T2D.
Methods and results: Type 2 diabetic (db ⁻ /db ⁻ ) and control (db ⁻ /db ⁺ ) mice were treated with two NFκB inhibitors (DHMEQ, 6mg/kg, twice a wee...
Objective: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In this study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension.
Methods & results: Mice were infused with angiotensin II (Ang-II, 400...
Epidermal growth factor receptor tyrosine kinase (EGFRtk) and endoplasmic reticulum (ER) stress are important factors in cardiovascular complications. Understanding whether enhanced EGFRtk activity and ER stress induction are involved in cardiac damage, and microvascular dysfunction in type 1 diabetes mellitus is an important question that has rema...
Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia-induced neovascularization in type II diabetes is unknown. We studied ischaemia-induced neovascularization in the hind-limb of 4-week-ol...
Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In the present study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension.
Mice were infused with angiotensin II (400 ng/kg per minute) with or with...
Vascular complications and cardiac damage are major cause of mortality in hypertension. In this study we explored the beneficial effect of ER stress inhibition on vascular and cardiac damage in hypertension
Mice were infused with Ang‐II with or without ER stress inhibitors (Tudca and PBA) for 2 weeks Mice infused with Ang‐II displayed an increase i...
Cardiovascular diseases are associated with endoplasmic reticulum (ER) stress. We have demonstrated that induction of ER stress in C57BL/6J, by the injection of tunicamycin, impairs vascular endothelium‐dependent relaxation (unpublished data).
In this study, we aimed to determine the mechanism by which ER stress reduces nitric oxide synthase activi...
Type 2 diabetes mellitus (T2DM) is associated with microvascular dysfunction. We hypothesized that increased poly(ADP-ribose) polymerase 1 (PARP-1) activity contributes to microvascular dysfunction in T2DM. T2DM (db(-)/db(-)) and nondiabetic control (db(-)/db(+)) mice were treated with 2 different PARP-1 inhibitors (INO-1001, 5 mg/kg per day and AB...
Type 2 diabetes is a key risk factor for ischemia-dependent pathology; therefore, a significant medical need exists to develop novel therapies that increase the formation of new vessels. We explored the therapeutic potential of epidermal growth factor receptor tyrosine kinase (EGFRtk) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitio...
We previously demonstrated that a reduced number of CD(4+)CD(25+)-regulatory T cells (Tregs) was associated with microvascular dysfunction in hypertension. However, the underlying mechanism by which Tregs regulate vascular endothelial function remains unknown.
Control and interleukin (IL)-10(-/-) knockout mice were infused with angiotensin II (400...
Objective
Type 2 diabetes is associated with microvascular dysfunction. We hypothesized that increased Poly‐(ADP‐ribose) polymerase 1 (PARP‐1) activity contributes to coronary arteriolar dysfunction.
Methods and Results
Type 2 diabetic db−/db− (diabetic) and non‐diabetic db−/db+ (control) mice were treated with PARP‐1 inhibitors (INO‐1001, 5mg/Kg/...
Exposure to mercury is known to increase cardiovascular risk but the underlying mechanisms are not well explored. We analysed whether chronic exposure to low mercury doses affects endothelial modulation of the coronary circulation.
Left coronary arteries and hearts from Wistar rats treated with either HgCl(2) (first dose 4.6 µg·kg(-1) , subsequent...
To assess whether angiotensin II (Ang II) modulates key enzymes of the cyclooxygenase (COX)-2/prostanoid pathway, including prostaglandin E synthase-1 (mPGES-1) and prostacyclin synthase (PGIS) in rat aortic adventitial fibroblasts in the presence or absence of an inflammatory stimulus [interleukin (IL)-1β].
Fibroblasts stimulated with IL-1β (10 ng...
Hepatocyte nuclear factor 1-α (HNF-1α) is a homeodomain transcription factor expressed in a variety of tissues (including liver and pancreas) that regulates a wide range of genes. Heterozygous mutations in the gene encoding HNF-1α (HNF1A) cause familial young-onset diabetes, also known as maturity-onset diabetes of the young, type 3 (MODY3). The va...
Glucokinase (GCK) acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. In the gene encoding GCK the heterozygous mutations that result in enzyme inactivation cause MODY2. Functional studies of naturally occurring GCK mutations associated with hyperglycaemia provide further insight into the biochemical basis of gluco...
Glucokinase acts as the pancreatic glucose sensor and plays a critical role in the regulation of insulin secretion by the beta-cell. Heterozygous mutations in the glucokinase-encoding GCK gene, which result in a reduction of the enzymatic activity, cause the monogenic form of diabetes, MODY2 (maturity-onset diabetes of the young 2). We have identif...
Adventitial layer plays a critical role in the regulation of vascular function and structure. Angiotensin II (Ang II) has been implicated in the pathophysiological processes that occur in hypertension through its significant proinflamatory actions in the vascular wall, including the production of inflammatory cytokines. Cyclooxygenase-2 (COX-2) and...