In vitro biological responses of plasma nanocoatings for coronary stent applications.

In-stent restenosis and thrombosis remain to be long-term challenges in coronary stenting procedures. The objective of this study was to evaluate the in vitro biological responses of trimethylsilane (TMS) plasma nanocoatings modified with NH /O (2:1 molar ratio) plasma post-treatment (TMS + NH /O nanocoatings) on cobalt chromium (CoCr) alloy L605 coupons, L605 stents, and 316L stainless steel (SS) stents. Surface properties of the plasma nanocoatings with up to 2-year aging time were characterized by wettability assessment and x-ray photoelectron spectroscopy (XPS).

K3.1 Inhibition Decreases Size and Alters Composition of Atherosclerotic Lesions Induced by Low, Oscillatory Flow.

Low, oscillatory flow/shear patterns are associated with atherosclerotic lesion development. Increased expression of K3.1 has been found in Vascular Smooth Muscle (VSM), macrophages and T-cells in lesions from humans and mice.

Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in K channels.

Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood.

Aldosterone impairs coronary adenosine-mediated vasodilation via reduced functional expression of Ca-activated K channels.

Elevated plasma aldosterone (Aldo) levels are associated with greater risk of cardiac ischemic events and cardiovascular mortality. Adenosine-mediated coronary vasodilation is a critical cardioprotective mechanism during ischemia; however, whether this response is impaired by increased Aldo is unclear. We hypothesized that chronic Aldo impairs coronary adenosine-mediated vasodilation via downregulation of vascular K channels.

Differential impact of severe familial hypercholesterolemia on regional skeletal muscle and organ blood flows during exercise: Effects of PDE5 inhibition.

Objective: Swine with familial hypercholesterolemia (FH) exhibit attenuated exercise-induced systemic vasodilation that is restored by phosphodiesterase 5 (PDE5) inhibition. Whether the impacts of FH and PDE5 inhibition to impair and restore exercise-induced vasodilation, respectively, results from tissue-specific or generalized effects remains unclear. Thus, we hypothesized that FH induces generalized impairment of skeletal muscle vasodilation that would be alleviated by PDE5 inhibition.

Endurance exercise training does not limit coronary atherosclerosis in familial hypercholesterolemic swine.

Human studies demonstrate that physical activity reduces both morbidity and mortality of coronary heart disease (CHD) including decreased progression and/or regression of CHD with life-style modification which includes exercise. However, evidence supporting an intrinsic, direct effect of exercise in attenuating the development of CHD is equivocal. One limitation has been the lack of a large animal model with clinically evident CHD disease.

KCa3.1 ion channel: A novel therapeutic target for corneal fibrosis.

Vision impairment from corneal fibrosis is a common consequence of irregular corneal wound healing after injury. Intermediate-conductance calmodulin/calcium-activated K+ channels 3.1 (KCa3.

Vascular cell transcriptomic changes to exercise training differ directionally along and between skeletal muscle arteriolar trees.

EXT-induced arteriolar adaptations in skeletal muscle are heterogeneous because of spatial variations in muscle fiber type composition and fiber recruitment patterns during exercise. The purpose of this report is to summarize a series of experiments conducted to test the hypothesis that changes in vascular gene expression are signaled by alterations in shear stress resulting from increases in blood flow, muscle fiber type composition, and fiber recruitment patterns. We also report results from a follow-up study of Ankrd23, one gene whose expression was changed by EXT.

Severe familial hypercholesterolemia impairs the regulation of coronary blood flow and oxygen supply during exercise.

Accelerated development of coronary atherosclerosis is a defining characteristic of familial hypercholesterolemia (FH). However, the recent data highlight a significant cardiovascular risk prior to the development of critical coronary stenosis. We, therefore, examined the hypothesis that FH produces coronary microvascular dysfunction and impairs coronary vascular control at rest and during exercise in a swine model of FH.

Reducing Neointima Formation in a Swine Model with IVUS and Sirolimus Microbubbles.

Potent therapeutic compounds with dose dependent side effects require more efficient and selective drug delivery to reduce systemic drug doses. Here, we demonstrate a new platform that combines intravascular ultrasound (IVUS) and drug-loaded microbubbles to enhance and localize drug delivery, while enabling versatility of drug type and dosing. Localization and degree of delivery with IVUS and microbubbles was assessed using fluorophore-loaded microbubbles and different IVUS parameters in ex vivo swine arteries.

Upregulation of intermediate-conductance Ca2+-activated K+ channels (KCNN4) in porcine coronary smooth muscle requires NADPH oxidase 5 (NOX5).

Aims: NADPH oxidase (NOX) is the primary source of reactive oxygen species (ROS) in vascular smooth muscle cells (SMC) and is proposed to play a key role in redox signaling involved in the pathogenesis of cardiovascular disease. Growth factors and cytokines stimulate coronary SMC (CSMC) phenotypic modulation, proliferation, and migration during atherosclerotic plaque development and restenosis. We previously demonstrated that increased expression and activity of intermediate-conductance Ca(2+)-activated K(+) channels (KCNN4) is necessary for CSMC phenotypic modulation and progression of stenotic lesions.

Localized in vivo model drug delivery with intravascular ultrasound and microbubbles.

An intravascular ultrasound (IVUS) and microbubble drug delivery system was evaluated in both ex vivo and in vivo swine vessel models. Microbubbles with the fluorophore DiI embedded in the shell as a model drug were infused into ex vivo swine arteries at a physiologic flow rate (105 mL/min) while a 5-MHz IVUS transducer applied ultrasound. Ultrasound pulse sequences consisted of acoustic radiation force pulses to displace DiI-loaded microbubbles from the vessel lumen to the wall, followed by higher-intensity delivery pulses to release DiI into the vessel wall.

Ovariectomy increases L-type Ca(2+) channel activity in porcine coronary smooth muscle.

Objective: Sex hormone status has been demonstrated to play a role in the regulation of ion channel activity. We previously demonstrated increased L-type Ca channel current (ICa) in the coronary smooth muscle cells (SMCs) of male swine compared with female swine. In male swine, endogenous testosterone increases ICa in SMCs by enhanced expression of the pore-forming α1 subunit Cav1.

Reduced contribution of endothelin to the regulation of systemic and pulmonary vascular tone in severe familial hypercholesterolaemia.

Vascular dysfunction has been associated with familial hypercholesterolaemia (FH), a severe form of hyperlipidaemia. We recently demonstrated that swine with FH exhibit reduced exercise-induced systemic, but not pulmonary, vasodilatation involving reduced nitric oxide (NO) bioavailability. Since NO normally limits endothelin (ET) action, we examined the hypothesis that reduced systemic vasodilatation during exercise in FH swine results from increased ET-mediated vasoconstriction.

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability.

Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation.

Carotid inflammation is unaltered by exercise in hypercholesterolemic Swine.

Introduction: Reduction of vascular inflammation might contribute to the beneficial effects of exercise. We hypothesized that 1) exercise would reduce carotid endothelial vascular cell adhesion molecule-1 (VCAM-1) and that 2) in vivo detection of carotid inflammation can be achieved in a large animal model using contrast-enhanced ultrasound (CEU) with VCAM-1-targeted microbubbles (MBs).

Methods: Familial hypercholesterolemic (FH) swine were divided into sedentary (Sed) and exercise-trained (Ex) groups.

The coronary circulation in exercise training.

Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. In large animals, EX increases capillary exchange capacity through angiogenesis of new capillaries at a rate matched to EX-induced cardiac hypertrophy so that capillary density remains normal. However, after EX coronary capillary exchange area is greater (i.

Hypercholesterolemia increases mitochondrial oxidative stress and enhances the MPT response in the porcine myocardium: beneficial effects of chronic exercise.

Hypercholesterolemia has been suggested to have direct negative effects on myocardial function due to increased reactive oxygen species (ROS) generation and increased myocyte death. Mitochondrial permeability transition (MPT) is a significant mediator of cell death, which is enhanced by ROS generation and attenuated by exercise training. The purpose of this study was to investigate the effect of hypercholesterolemia on the MPT response of cardiac mitochondria.

Impact of exercise training on endothelial transcriptional profiles in healthy swine: a genome-wide microarray analysis.

While the salutary effects of exercise training on conduit artery endothelial cells have been reported in animals and humans with cardiovascular risk factors or disease, whether a healthy endothelium is alterable with exercise training is less certain. The purpose of this study was to evaluate the impact of exercise training on transcriptional profiles in normal endothelial cells using a genome-wide microarray analysis. Brachial and internal mammary endothelial gene expression was compared between a group of healthy pigs that exercise trained for 16-20 wk (n = 8) and a group that remained sedentary (n = 8).

Store-operated Ca(2+) entry is not essential for PDGF-BB induced phenotype modulation in rat aortic smooth muscle.

Suppression of smooth muscle cell (SMC) differentiation marker genes is central to SMC phenotype modulation during vasculo-proliferative diseases such as atherosclerosis and restenosis. Upregulation of the intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) is integral for mitogen-induced suppression of SMC marker genes and post-angioplasty restenosis.

Focused in vivo delivery of plasmid DNA to the porcine vascular wall via intravascular ultrasound destruction of microbubbles.

Background: Safety concerns associated with drug-eluting stents have spurred interest in alternative vessel therapeutics following angioplasty. Microbubble contrast agents have been shown to increase gene transfection in vivo in the presence of ultrasound.

Objectives/methods: The purpose of this study was to determine whether an intravascular ultrasound (IVUS) catheter could mediate plasmid DNA transfection from microbubble carriers to the porcine coronary artery wall following balloon angioplasty.

The smooth muscle cell-restricted KCNMB1 ion channel subunit is a direct transcriptional target of serum response factor and myocardin.

Large conductance calcium-activated potassium (MaxiK) channels play a pivotal role in maintaining normal arterial tone by regulating the excitation-contraction coupling process. MaxiK channels comprise alpha and beta subunits encoded by Kcnma and the cell-restricted Kcnmb genes, respectively. Although the functionality of MaxiK channel subunits has been well studied, the molecular regulation of their transcription and modulation in smooth muscle cells (SMCs) is incomplete.

Exercise training decreases the size and alters the composition of the neointima in a porcine model of percutaneous transluminal coronary angioplasty (PTCA).

Exercise training (EX) following percutaneous transluminal coronary angiography (PTCA) reduces progression to restenosis and increases event-free survival rates. Our aim was to determine whether EX inhibits lesion development and/or alters the extracellular matrix (ECM) composition of the neointima (NI) in a porcine PTCA model. Miniature Yucatan swine were assigned to cage confinement (SED) or EX for 20 wk.