elastin and Metabolic-Syndrome

The Cardiovascular Continuum describes a sequence of events from cardiovascular risk factors to end-stage heart disease. It includes conventional pathologies affecting cardiovascular functions such as hypertension, atherosclerosis or thrombosis and was traditionally considered from the metabolic point of view. This Cardiovascular Continuum, originally described by Dzau and Braunwald, was extended by O'Rourke to consider also the crucial role played by degradation of elastic fibers, occurring during aging, in the appearance of vascular stiffness, another deleterious risk factor of the continuum. However, the involvement of the elastin degradation products, named elastin-derived peptides, to the Cardiovascular Continuum progression has not been considered before. Data from our laboratory and others clearly showed that these bioactive peptides are central regulators of this continuum, thereby amplifying appearance and evolution of cardiovascular risk factors such as diabetes or hypertension, of vascular alterations such as atherothrombosis and calcification, but also nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The Elastin Receptor Complex has been shown to be a crucial actor in these processes. We propose here the participation of these elastin-derived peptides and of the Elastin Receptor Complex in these events, and introduce a revisited Cardiovascular Continuum based on their involvement, for which elastin-based pharmacological strategies could have a strong impact in the future.

Topics: Animals; Cardiovascular Diseases; Elastin; Humans; Metabolic Syndrome; Peptides; Receptors, Cell Surface

Arterial stiffness is an independent risk factor for premature cardiovascular morbidity and mortality that can be evaluated by noninvasive methods and can be reduced by good clinical management. The present chapter examines the association between arterial stiffness and cardiovascular risk factors including hypertension, metabolic syndrome, diabetes, advanced renal failure, hypercholesterolemia and obesity. The mechanisms responsible for the structural and functional modifications of the arterial wall are also described. We deal with parameters related to arterial compliance, focusing on two of them, pulse wave velocity and the augmentation index, useful in rapid assessment of arterial compliance by the bedside. Data that highlight the role of aortic pulse wave velocity and the augmentation index as independent factors in predicting fatal and nonfatal cardiovascular events in different populations are briefly presented. A number of lifestyle changes and traditional antihypertensive agents that improve arterial compliance are finally discussed. Novel therapies, such as statins, thiazolidindinediones, phosphodiesterase inhibitors and inhibitors or breakers of advanced glycation end product cross-links between colagen and elastin hold substantial promise.

Topics: Arteries; Blood Pressure; Cardiovascular Diseases; Diabetic Angiopathies; Elasticity; Elastin; Fibronectins; Humans; Hypertension; Matrix Metalloproteinases; Metabolic Syndrome; Obesity; Proteoglycans; Pulse

The vascular endothelial basement membrane and extra cellular matrix is a compilation of different macromolecules organized by physical entanglements, opposing ionic charges, chemical covalent bonding, and cross-linking into a biomechanically active polymer. These matrices provide a gel-like form and scaffolding structure with regional tensile strength provided by collagens, elasticity by elastins, adhesiveness by structural glycoproteins, compressibility by proteoglycans--hyaluronans, and communicability by a family of integrins, which exchanges information between cells and between cells and the extracellular matrix of vascular tissues. Each component of the extracellular matrix and specifically the capillary basement membrane possesses unique structural properties and interactions with one another, which determine the separate and combined roles in the multiple diabetic complications or diabetic opathies. Metabolic syndrome, prediabetes, type 2 diabetes mellitus, and their parallel companion (atheroscleropathy) are associated with multiple metabolic toxicities and chronic injurious stimuli. The adaptable quality of a matrix or form genetically preloaded with the necessary information to communicate and respond to an ever-changing environment, which supports the interstitium, capillary and arterial vessel wall is individually examined.

Topics: Basement Membrane; Cardiovascular System; Collagen; Diabetes Mellitus, Type 2; Elastin; Endothelium, Vascular; Extracellular Matrix; Glycoproteins; Humans; Integrins; Matrix Metalloproteinases; Metabolic Syndrome; Pericytes; Protein Kinase C

Annular elastolytic giant cell granuloma (AEGCG) is a rare granulomatous skin condition. It belongs to a group of skin and elastic fiber disorders. When it affects sun-exposed skin, it is also called actinic granuloma. The etiology and pathogenesis are still debated. However, sun-induced actinic damage to elastic fibers is acknowledged as the primary triggering factor, though the pathogenesis of instances in sun-covered areas is unknown. The most commonly linked systemic illness is diabetes mellitus. Different case reports show an association of this disease with hematological conditions, infections, sarcoidosis, and protoporphyria. Multisystemic involvement was also reported in a case. The disease is clinically recognized by erythematous non-scaly annular patches and plaques with raised borders and hypopigmented or skin-colored centers, sometimes atrophic. It is usually asymptomatic or mildly itchy. The presence of an inflammatory infiltration with non-palisading granulomas, multinucleate large cells, elastin degradation, and elastophagocytosis, as well as the absence of necrobiosis and mucin, are histopathological characteristics. We report a 5-year history of annular elastolytic giant cell granuloma in a 66-year-old woman with a history of type two diabetes mellitus, hypertension, and fatty liver disease (steatosis). She presented with asymptomatic polymorphic erythematous skin lesions mainly in sun-exposed areas.

Topics: Aged; Diabetes Mellitus; Elastin; Female; Granuloma, Giant Cell; Humans; Metabolic Syndrome; Mucins; Photosensitivity Disorders

Arterial stiffness plays a causal role in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome P450 (CYP450)-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and loosely associated with obesity in humans. However, the role of 20-HETE in the regulation of large artery remodeling in metabolic syndrome has not been investigated. We hypothesized that elevated 20-HETE in metabolic syndrome increases matrix metalloproteinase 12 (MMP12) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure. 20-HETE production was increased ~7 fold in large, conduit arteries of metabolic syndrome (JCR:LA-cp, JCR) vs. normal Sprague-Dawley (SD) rats. This correlated with increased elastin degradation (~7 fold) and decreased arterial compliance (~75% JCR vs. SD). 20-HETE antagonists blocked elastin degradation in JCR rats concomitant with blocking MMP12 activation. 20-HETE antagonists normalized, and MMP12 inhibition (pharmacological and MMP12-shRNA-Lnv) significantly improved (~50% vs. untreated JCR) large artery compliance in JCR rats. 20-HETE antagonists also decreased systolic (182 ± 3 mmHg JCR, 145 ± 3 mmHg JCR + 20-HETE antagonists) but not diastolic blood pressure in JCR rats. Whereas diastolic pressure was fully angiotensin II (Ang II)-dependent, systolic pressure was only partially Ang II-dependent, and large artery stiffness was Ang II-independent. Thus, 20-HETE-dependent regulation of systolic blood pressure may be a unique feature of metabolic syndrome related to high 20-HETE production in large, conduit arteries, which results in increased large artery stiffness and systolic blood pressure. These findings may have implications for management of systolic hypertension in patients with metabolic syndrome.

Topics: Animals; Blood Pressure; Collagen Type I; Collagen Type III; Compliance; Cytochrome P-450 CYP4A; Cytochrome P450 Family 4; Diastole; Elastin; Enzyme Activation; Hydroxyeicosatetraenoic Acids; Hypertension; Losartan; Male; Matrix Metalloproteinase 12; Metabolic Syndrome; Proteolysis; Rats, Sprague-Dawley; RNA, Small Interfering; Vascular Stiffness

Mineralocorticoid receptor (MR) expression is increased in adipose tissue from obese individuals and animals. We previously demonstrated that adipocyte-MR overexpression (Adipo-MROE) in mice is associated with metabolic changes. Whether adipocyte MR directly influences vascular function in these mice is unknown. We tested this hypothesis in resistant mesenteric arteries from Adipo-MROE mice using myography and in cultured adipocytes. Molecular mechanisms were probed in vessels/vascular smooth muscle cells and adipose tissue/adipocytes and focused on redox-sensitive pathways, Rho kinase activity, and protein kinase G type-1 (PKG-1) signaling. Adipo-MROE versus control-MR mice exhibited reduced vascular contractility, associated with increased generation of adipocyte-derived hydrogen peroxide, activation of vascular redox-sensitive PKG-1, and downregulation of Rho kinase activity. Associated with these vascular changes was increased elastin content in Adipo-MROE. Inhibition of PKG-1 with Rp-8-Br-PET-cGMPS normalized vascular contractility in Adipo-MROE. In the presence of adipocyte-conditioned culture medium, anticontractile effects of the adipose tissue were lost in Adipo-MROE mice but not in control-MR mice. In conclusion, adipocyte-MR upregulation leads to impaired contractility with preserved endothelial function and normal blood pressure. Increased elasticity may contribute to hypocontractility. We also identify functional cross talk between adipocyte MR and arteries and describe novel mechanisms involving redox-sensitive PKG-1 and Rho kinase. Our results suggest that adipose tissue from Adipo-MROE secrete vasoactive factors that preferentially influence vascular smooth muscle cells rather than endothelial cells. Our findings may be important in obesity/adiposity where adipocyte-MR expression/signaling is amplified and vascular risk increased.

Topics: Adipocytes; Aldosterone; Angiotensin II; Animals; Cells, Cultured; Corticosterone; Culture Media, Conditioned; Elastin; Humans; Intra-Abdominal Fat; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Oxidation-Reduction; Phosphorylation; Receptors, Mineralocorticoid; rho-Associated Kinases

Previous studies from our laboratory showed that coronary arterioles from type 2 diabetic mice undergo inward hypertrophic remodeling and reduced stiffness. The aim of the current study was to determine if coronary resistance microvessels (CRMs) in Ossabaw swine with metabolic syndrome (MetS) undergo remodeling distinct from coronary conduit arteries. Male Ossabaw swine were fed normal (n = 7, Lean) or hypercaloric high-fat (n = 7, MetS) diets for 6 mo, and then CRMs were isolated and mounted on a pressure myograph. CRMs isolated from MetS swine exhibited decreased luminal diameters (126 ± 5 and 105 ± 9 μm in Lean and MetS, respectively, P < 0.05) with thicker walls (18 ± 3 and 31 ± 3 μm in Lean and MetS, respectively, P < 0.05), which doubled the wall-to-lumen ratio (14 ± 2 and 30 ± 2 in Lean and MetS, respectively, P < 0.01). Incremental modulus of elasticity (IME) and beta stiffness index (BSI) were reduced in CRMs isolated from MetS pigs (IME: 3.6 × 10(6) ± 0.7 × 10(6) and 1.1 × 10(6) ± 0.2 × 10(6) dyn/cm(2) in Lean and MetS, respectively, P < 0.001; BSI: 10.3 ± 0.4 and 7.3 ± 1.8 in Lean and MetS, respectively, P < 0.001). BSI in the left anterior descending coronary artery was augmented in pigs with MetS. Structural changes were associated with capillary rarefaction, decreased hyperemic-to-basal coronary flow velocity ratio, and augmented myogenic tone. MetS CRMs showed a reduced collagen-to-elastin ratio, while immunostaining for the receptor for advanced glycation end products was selectively increased in the left anterior descending coronary artery. These data suggest that MetS causes hypertrophic inward remodeling of CRMs and capillary rarefaction, which contribute to decreased coronary flow and myocardial ischemia. Moreover, our data demonstrate novel differential remodeling between coronary micro- and macrovessels in a clinically relevant model of MetS.

Topics: Animals; Blood Flow Velocity; Collagen; Coronary Circulation; Coronary Vessels; Elastin; Male; Metabolic Syndrome; Microvessels; Obesity; Swine