Reactive Oxygen-Forming Nox5 Links Vascular Smooth Muscle Cell Phenotypic Switching and Extracellular Vesicle-Mediated Vascular Calcification.

Rationale: Vascular calcification, the formation of calcium phosphate crystals in the vessel wall, is mediated by vascular smooth muscle cells (VSMCs). However, the underlying molecular mechanisms remain elusive, precluding mechanism-based therapies.

Objective: Phenotypic switching denotes a loss of contractile proteins and an increase in migration and proliferation, whereby VSMCs are termed synthetic.

An ADAM33 polymorphism associates with progression of preschool wheeze into childhood asthma: a prospective case-control study with replication in a birth cohort study.

Background: The influence of asthma candidate genes on the development from wheeze to asthma in young children still needs to be defined.

Objective: To link genetic variants in asthma candidate genes to progression of wheeze to persistent wheeze into childhood asthma.

Materials And Methods: In a prospective study, children with recurrent wheeze from the ADEM (Asthma DEtection and Monitoring) study were followed until the age of six.

Protein kinase-D1 overexpression prevents lipid-induced cardiac insulin resistance.

In the insulin resistant heart, energy fuel selection shifts away from glucose utilization towards almost complete dependence on long-chain fatty acids (LCFA). This shift results in excessive cardiac lipid accumulation and eventually heart failure. Lipid-induced cardiomyopathy may be averted by strategies that increase glucose uptake without elevating LCFA uptake.

Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma.

Background: Childhood asthma is characterized by chronic airway inflammation. Integrative genomic analysis of airway inflammation on genetic and protein level may help to unravel mechanisms of childhood asthma. We aimed to employ an integrative genomic approach investigating inflammation markers on DNA, mRNA, and protein level at preschool age in relationship to asthma development.

A systematic review of CD14 and toll-like receptors in relation to asthma in Caucasian children.

The aetiology of childhood asthma is complex. An early dysfunction in the immunological development of the innate immune system in combination with environmental factors possibly triggers asthma. CD14 and toll-like receptors are important components of the innate immune system.

Overexpression of AMP-activated protein kinase or protein kinase D prevents lipid-induced insulin resistance in cardiomyocytes.

During lipid oversupply, the heart becomes insulin resistant, as exemplified by defective insulin-stimulated glucose uptake, and will develop diastolic dysfunction. In the healthy heart, not only insulin, but also increased contractile activity stimulates glucose uptake. Upon increased contraction both AMP-activated protein kinase (AMPK) and protein kinase D (PKD) are activated, and mediate the stimulation of glucose uptake into cardiomyocytes.

Overexpression of vesicle-associated membrane protein (VAMP) 3, but not VAMP2, protects glucose transporter (GLUT) 4 protein translocation in an in vitro model of cardiac insulin resistance.

Cardiac glucose utilization is regulated by reversible translocation of the glucose transporter GLUT4 from intracellular stores to the plasma membrane. During the onset of diet-induced insulin resistance, elevated lipid levels in the circulation interfere with insulin-stimulated GLUT4 translocation, leading to impaired glucose utilization. Recently, we identified vesicle-associated membrane protein (VAMP) 2 and 3 to be required for insulin- and contraction-stimulated GLUT4 translocation, respectively, in cardiomyocytes.

Protein kinase D increases maximal Ca2+-activated tension of cardiomyocyte contraction by phosphorylation of cMyBP-C-Ser315.

Cardiac myosin-binding protein C (cMyBP-C) is involved in the regulation of cardiac myofilament contraction. Recent evidence showed that protein kinase D (PKD) is one of the kinases that phosphorylate cMyBP-C. However, the mechanism by which PKD-induced cMyBP-C phosphorylation affects cardiac contractile responses is not known.

Protein kinase D1 is essential for contraction-induced glucose uptake but is not involved in fatty acid uptake into cardiomyocytes.

Increased contraction enhances substrate uptake into cardiomyocytes via translocation of the glucose transporter GLUT4 and the long chain fatty acid (LCFA) transporter CD36 from intracellular stores to the sarcolemma. Additionally, contraction activates the signaling enzymes AMP-activated protein kinase (AMPK) and protein kinase D1 (PKD1). Although AMPK has been implicated in contraction-induced GLUT4 and CD36 translocation in cardiomyocytes, the precise role of PKD1 in these processes is not known.

High fat diet induced diabetic cardiomyopathy.

In response to a chronic high plasma concentration of long-chain fatty acids (FAs), the heart is forced to increase the uptake of FA at the cost of glucose. This switch in metabolic substrate uptake is accompanied by an increased presence of the FA transporter CD36 at the cardiac plasma membrane and over time results in the development of cardiac insulin resistance and ultimately diabetic cardiomyopathy. FA can interact with peroxisome proliferator-activated receptors (PPARs), which induce upregulation of the expression of enzymes necessary for their disposal through mitochondrial β-oxidation, but also stimulate FA uptake.

Postpartum reversal of the pregnancy-induced uterine artery remodeling in young, aging, and eNOS-deficient mice.

Objectives: The progressive rise in uterine blood flow (UBF) during pregnancy is accompanied by outward hypertrophic remodeling of the uterine artery (UA). After birth, UBF falls in concert with the sudden decline in uterine metabolic demands. Arterial remodeling associated with the reversal of increased blood flow has been described in large arteries.

Smoothelin-B deficiency results in reduced arterial contractility, hypertension, and cardiac hypertrophy in mice.

Background: Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B(-/-) mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction.

Cytostatic drugs differentially affect phenotypic features of porcine coronary artery smooth muscle cell populations.

We studied the effects of cytostatic drugs on porcine coronary artery spindle-shaped (S) and rhomboid (R) smooth muscle cell (SMC) biological activities related to intimal thickening (IT) formation. Imatinib, and to a lesser extent curcumin, decreased proliferation of S- and R-SMCs and migratory and urokinase activities of R-SMCs more efficiently compared with cyclosporine plus rapamycin. Imatinib increased the expression of alpha-smooth muscle actin in both SMC populations and that of smoothelin in S-SMCs.

Evaluation of manual and automatic segmentation of the mouse heart from CINE MR images.

Purpose: To compare global functional parameters determined from a stack of cinematographic MR images of mouse heart by a manual segmentation and an automatic segmentation algorithm.

Materials And Methods: The manual and automatic segmentation results of 22 mouse hearts were compared. The automatic segmentation was based on propagation of a minimum cost algorithm in polar space starting from manually drawn contours in one heart phase.

Smoothelin in vascular smooth muscle cells.

Smoothelin-A and -B have only been found in fully differentiated contractile smooth muscle cells. They are increasingly used to monitor the smooth muscle cell differentiation process to a contractile or synthetic phenotype. Vascular-specific smoothelin-B is the first smooth muscle cell marker that disappears when vascular tissues are compromised, for example, in atherosclerosis or restenosis.

Comparison between prospective and retrospective triggering for mouse cardiac MRI.

High-resolution magnetic resonance imaging (MRI) has evolved into one of the major non-invasive tools to study the healthy and diseased mouse heart. This study presents a Cartesian CINE MRI protocol based on a fast low-angle shot sequence with a navigator echo to generate cardiac triggering and respiratory gating signals retrospectively, making the use of ECG leads and respiratory motion sensors obsolete. MRI of the in vivo mouse heart using this sequence resulted in CINE images with no detectable cardiac and respiratory motion artefacts.

Estrogen receptor beta protects the murine heart against left ventricular hypertrophy.

Background: Left ventricular hypertrophy (LVH) displays significant gender-based differences. 17beta-estradiol (E2) plays an important role in this process because it can attenuate pressure overload hypertrophy via 2 distinct estrogen receptors (ERs): ERalpha and ERbeta. However, which ER is critically involved in the modulation of LVH is poorly understood.

Contribution of serum response factor and myocardin to transcriptional regulation of smoothelins.

Objective: Smoothelin-A and -B isoforms are highly restricted to contractile smooth muscle cells (SMCs). Serum response factor (SRF) and myocardin are essential for contractile SMC differentiation. We evaluated the contribution of SRF/myocardin to transcriptional regulation of smoothelins.

Smoothelin-a is essential for functional intestinal smooth muscle contractility in mice.

Background & Aims: In patients with chronic intestinal pseudo-obstruction, intestinal motility is disturbed by either nervous or myogenic aberrations. The cause of the myogenic form is unknown, but it is likely to originate in the contractile apparatus of the smooth muscle cells. Smoothelins are actin-binding proteins that are expressed abundantly in visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle.

Vascular expression of adrenomedullin is increased in Wistar rats during early pregnancy.

Objective: Circulating levels of adrenomedullin (ADM)--a vasodilator peptide with long-lasting effects--increase in the course of pregnancy. Neither the site nor the concomitant rate of ADM synthesis in pregnancy is known. The aim of this study was to test the hypothesis that the rise in plasma levels of ADM during pregnancy is paralleled by increased gene expression and protein levels in the vascular bed.

Uterine artery remodeling in pseudopregnancy is comparable to that in early pregnancy.

During pregnancy, the lumenal diameter and wall mass of the uterine artery (UA) increase, most likely in response to the increased hemodynamic strain resulting from the chronically elevated uterine blood flow (UBF). In this remodeling process, the phenotype of vascular smooth-muscle cells (VSMC) is transiently altered to enable VSMC proliferation. These phenomena are already seen during early pregnancy, when the rise in UBF is still modest.

Uterine artery remodeling and reproductive performance are impaired in endothelial nitric oxide synthase-deficient mice.

The progressive rise in uterine blood flow during pregnancy is accompanied by outward hypertrophic remodeling of the uterine artery (UA). This process involves changes of the arterial smooth muscle cells and extracellular matrix. Acute increases in blood flow stimulate endothelial production of nitric oxide (NO).

Troponin I isoform expression in human and experimental atrial fibrillation.

Background: Atrial fibrillation (AF) is accompanied by re-expression of fetal genes and activation of proteolytic enzymes. In this study both aspects were addressed with respect to troponin I (TnI) isoform expression.

Methods And Results: Western blotting and real-time reverse transcription-polymerase chain reaction were used to study TnI isoform expression in patients with paroxysmal or chronic AF and in goats after 1, 2, 4, 8, and 16 weeks of AF.