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Biomedical subjects

Lucia Mazzolai

Publications and source records attributed to Lucia Mazzolai.

11 recordsLinked to original sources
PubMed2007

Endothelial function, mechanical stress and atherosclerosis.

Atherosclerosis and its complications represent the leading cause of morbidity and mortality in the industrialized as well as in the developing countries. Classical cardiovascular risk factors have been identified over the past decades leading to recommendations for life style modifications and to the development of efficient and well-tolerated drug regimens aimed at reducing the occurrence of cardiovascular complications. The endothelium due to its position in the circulation is the first organ being exposed to circulating noxious elements and solutes as well as to the mechanical aggressions generated by heartbeats and pulsating blood flow. This review addresses the relevance of the combined effects of the mechanical stress and cardiovascular risk factors on the early phases of atherosclerosis.

Age Factors↗
PubMed2006

Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy.

Heparin is the drug of choice for the treatment or the prevention of thromboembolic disease during pregnancy. However, treatment options are limited when heparin cannot be used because of hypersensitivity skin reactions. Despite the recent availability of new anticoagulant agents, data relating to their use during pregnancy are lacking. This report describes the successful management with fondaparinux, during 150 days, of a pregnant patient with protein S deficiency and prior deep vein thrombosis (DVT) who developed heparin and danaparoid hypersensitivity.

Adult↗
PubMed2006

The renin-angiotensin system and atherosclerosis.

Atherosclerosis is an insidious and complex disease of large- and medium-sized arteries. The primum movens of the disease is characterized by co-localization of lipids, inflammatory cells, and fibrous elements within the intima of vessels. Starting as a "fatty streak," the disease evolves over decades into complex lesions that can progress toward a stable or a vulnerable plaque. During the past decade, we have become familiar with the features of the vulnerable plaque; however, the mechanisms that cause a stable plaque to change into a vulnerable lesion with its dramatic clinical outcome still remain largely unknown. There is good evidence from epidemiologic, experimental, and clinical studies that the renin-angiotensin system, via its active peptide angiotensin II, may contribute to atherosclerosis development and progression, not only by increasing blood pressure but also through multiple direct effects. Moreover, recent studies have shown a potential role for angiotensin II as a mediator of plaque vulnerability.

Animals↗
PubMed2005

Severe hyperlipidemia causes impaired renin-angiotensin system function in apolipoprotein E deficient mice.

Dyslipidemia is a known risk factor for cardiovascular diseases and may associate with renal injury. Using mouse models with various degrees of hypercholesterolemia and hypertryliceridemia, we investigated the effects of lipids on the renin-angiotensin system (RAS). ApoE-/- mice were fed either a high fat diet (HF-ApoE-/-; mice developed hypertriglyceridemia and severe hypercholesterolemia) or regular chow (R-ApoE(-/-); mice developed less severe hypercholesterolemia only). Renal histopathology in the HF-ApoE-/- revealed massive lipid accumulation especially at the glomerular vascular pole. In these mice plasma renin concentration was significantly reduced (489+/-111 ng/(ml h) versus 1023+/-90 ng/(ml h) in R-ApoE-/- mice) and blood pressure was consequently significantly lower than in R-ApoE-/- (104+/-2 mmHg versus 115+/-2 mmHg, respectively). A model of renin-dependent renovascular hypertension (two-kidney, one clip) was generated and HF-ApoE-/- mice proved unable to increase renin secretion, and blood pressure, in response to diminished renal perfusion as compared to regular chow fed mice (665+/-90 ng/(ml h) versus 2393+/-372 ng/(ml h), respectively and 106+/-3 mmHg versus 140+/-2 mmHg, respectively). Hypertriglyceridemia and severe hypercholesterolemia are associated with renal lipid deposition and impaired renin secretion in ApoE-/- mice exposed to high fat diet. These observations further characterize the phenotype of this widely used mouse model and provide a rationale for the use of these mice to study lipid induced organ damage.

Animals↗
PubMed2004

Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction.

BACKGROUND: Arginase competes with endothelial nitric oxide synthase (eNOS) for the substrate l-arginine and decreases NO production. This study investigated regulatory mechanisms of arginase activity in endothelial cells and its role in atherosclerosis. METHODS AND RESULTS: In human endothelial cells isolated from umbilical veins, thrombin concentration- and time-dependently stimulated arginase enzymatic activity, reaching a 1.9-fold increase (P<0.001) at 1 U/mL for 24 hours. The effect of thrombin was prevented by C3 exoenzyme or the HMG-CoA reductase inhibitor fluvastatin, which inhibit RhoA, or by the ROCK inhibitors Y-27632 and HA-1077. Adenoviral expression of constitutively active RhoA or ROCK mutants enhanced arginase activity (approximately 3-fold, P<0.001), and the effect of active RhoA mutant was inhibited by the ROCK inhibitors. Neither thrombin nor the active RhoA/ROCK mutants affected arginase II protein level, the only isozyme detectable in the cells. Moreover, a significantly higher arginase II activity (1.5-fold, not the protein level) and RhoA protein level (4-fold) were observed in atherosclerotic aortas of apoE-/- compared with wild-type mice. Interestingly, l-arginine (1 mmol/L), despite a significantly higher eNOS expression in aortas of apoE-/- mice, evoked a more pronounced contraction, which was reverted to a greater vasodilation by the arginase inhibitor l-norvaline (20 mmol/L) compared with the wild-type animals (n=5, P<0.001). CONCLUSIONS: Thrombin enhances arginase activity via RhoA/ROCK in human endothelial cells. Higher arginase enzymatic activity is involved in atherosclerotic endothelial dysfunction in apoE-/- mice. Targeting vascular arginase may represent a novel therapeutic possibility for atherosclerosis.

Animals↗
PubMed2004

Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE-/- mice.

Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis. To study the contribution of angiotensin II in plaque vulnerability, we generated hypertensive hypercholesterolemic ApoE-/- mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE-/- mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE-/- mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE-/- mice had thinner fibrous cap (P<0.01), larger lipid core (P<0.01), and increased macrophage content (P<0.01) than even more hypertensive but normal angiotensin II ApoE-/- mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE-/- mice produced significantly higher amounts of interferon (IFN)-gamma than those from ApoE-/- mice with normal angiotensin II; secretion of IL4 and IL10 was not different. In addition, we provide evidence for a direct stimulating effect of angiotensin II on lymphocyte IFN-gamma production. These findings suggest a new mechanism in plaque vulnerability demonstrating that angiotensin II, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator promoting the induction of vulnerable plaques probably via a T helper switch.

Angiotensin II↗
PubMed2003

Blood sampling methodology is crucial for precise measurement of plasma catecholamines concentrations in mice.

Epinephrine (E) and norepinephrine (NE) play a major role in regulating metabolism and cardiovascular physiology. Both are secreted in response to stress and their measurement in plasma allows the study of sympathoadrenal function. Several studies investigating sympathoadrenal physiology are conducted using mice. Review of the literature revealed that basal mouse NE and E plasma concentrations range within 4-140 nM depending on the blood sampling method. Such variability doesn't allow study comparison and may conceal catecholamine variations in response to stress. Therefore, our aim was to determine a reliable sampling method to measure mouse plasma catecholamine concentrations. Results showed that arterial catheterization is the most accurate sampling method: E and NE basal levels were similar to those found in humans (1.1+/-0.3 nM and 4.1+/-0.5 nM, respectively). Retro-orbital bleeding led to analogous results. On the contrary, decapitation was stressful for mice and consequently NE and E concentrations were high (24.6+/-2.7 nM and 27.3+/-3.8 nM, respectively). These different bleeding methods were compared in terms of their ability to detect sympathoadrenal system stimulation (cold-pressure test). With catheter and retro-orbital samplings the expected increase in NE and E levels was easily perceived. In contrast, with decapitation no significant change in E was detected. In conclusion, arterial-catheter and retro-orbital blood sampling methods appear to be the most accurate procedures for studying the sympathetic nervous system in mice in both unstressed and stressed conditions.

Animals↗
PubMed2003

ET-1 and NOS III gene expression regulation by plaque-free and plaque-prone hemodynamic conditions.

Both plaque-free and plaque-prone hemodynamic environments induce an increase in the oxidative state of endothelial cells (ECs), whereas differential gene expression regulation was described in cells exposed to these conditions. In order to investigate the role of the increased oxidative state in flow-regulation of gene expression, we first exposed EC to non-pulsed unidirectional shear stress. These conditions only slightly increases ECs oxidative state and endothelin-1 (ET-1) mRNA expression, whereas endothelial nitric oxide synthase (NOS III) mRNA level were significantly up-regulated. On the contrary, both ET-1 and NOS III gene expression were significantly induced in EC exposed to pulsed-unidirectional flow (plaque-free). Only ET-1 gene expression was up-regulated by oscillatory flow (plaque-prone). Moreover, use of an antioxidant only partially inhibited NOS III gene up-regulation by unidirectional flow, whereas it completely abrogated ET-1 gene up-regulation by unidirectional and oscillatory flows. Thus suggesting that mechanical forces regulate gene expression in ECs both via oxidative stress-dependent and -independent mechanisms.

Animals↗
PubMed2002

Tissue factor activity is upregulated in human endothelial cells exposed to oscillatory shear stress.

Hemodynamic forces play a critical role in the pathogenesis of atherosclerosis as evidenced by the focal nature of the disease. Oscillatory shear stress characterizes the hemodynamic environment of plaque-prone areas as opposed to unidirectional shear stress typical of plaque-free areas. These particular flow conditions modulate atherosclerosis-related genes. Tissue factor (TF) initiates blood coagulation, contributes to vascular remodeling, and is therefore a potential contributor in the development/progression of atherosclerosis. We investigated the effect of oscillatory and unidirectional flows on TF using an in vitro perfusion system. Human endothelial cells exposed for 24 h to oscillatory shear stress, significantly increased TF mRNA, and TF protein expression (1.5- and 1.75-fold, respectively, p < 0.01), and surface TF activity (twofolds-increase). Expression of TF inhibitor (TFPI), mRNA and protein, remained unchanged as compared to static conditions. Conversely, cells exposed to unidirectional shear, showed a decrease in TF activity with a significant increase in TFPI mRNA and protein expression (1.5- and 1.8-fold, respectively, p < 0.01). These results show for the first time that pulsatile oscillatory shear stress induces a pro-coagulant phenotype of endothelial cells which may favor formation/progression of atherothrombotic lesions.

Apoptosis↗
PubMedDate not supplied

Comparison of morphological and functional alterations of human saphenous veins after seven and fourteen days of ex vivo perfusion.

Intimal hyperplasia (IH) is a vessel wall remodeling process responsible of early failure after vascular surgery or endovascular interventions. An ex vivo perfusion was used to study human venous segments regarding functional, histomorphological, immunohistochemical and molecular alterations after 7 (group 1, n = 6) and 14 days (group 2, n = 6) of ex vivo perfusion. All vessel segments showed preserved smooth muscle function before and after perfusion. Histomorphometry revealed IH development which was more pronounced after 14 days rather than 7 days (p < 0.05). Expression of CD34, factor VIII, alpha-actin and MIB-1 was demonstrated in all segments from both groups indicating that muscular and endothelial integrity was preserved after ex vivo perfusion of up to 14 days. PAI-1 mRNA expression was significantly increased after perfusion (p < 0.05), suggesting that the endothelial fibrinolytic function may be modulated in this ex vivo perfusion model of human saphenous veins.

Actins↗