Toll-Like Receptor 3 Mediates Aortic Stenosis Through a Conserved Mechanism of Calcification.

Background: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation.

NADPH oxidases and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess.

Cardiovascular side effects are frequent problems accompanying systemic glucocorticoid therapy, although the underlying mechanisms are not fully resolved. Reactive oxygen species (ROS) have been shown to promote various cardiovascular diseases although the link between glucocorticoid and ROS signaling has been controversial. As the family of NADPH oxidases has been identified as important source of ROS in the cardiovascular system we investigated the role of NADPH oxidases in response to the synthetic glucocorticoid dexamethasone in the cardiovascular system in vitro and in vivo in mice lacking functional NADPH oxidases due to a mutation in the gene coding for the essential NADPH oxidase subunit p22phox.

Stabilization of p22phox by Hypoxia Promotes Pulmonary Hypertension.

Aims: Hypoxia and reactive oxygen species (ROS) have been shown to play a role in the pathogenesis of pulmonary hypertension (PH), a potentially fatal disorder characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right ventricular hypertrophy. However, how they are linked in the context of PH is not completely understood. We, therefore, investigated the role of the NADPH oxidase subunit p22phox in the response to hypoxia both in vitro and in vivo.

Cross Talk Between p22phox and ATF4 in the Endothelial Unfolded Protein Response.

Background: Cardiovascular diseases have been associated with stress in the endoplasmic reticulum (ER) and accumulation of unfolded proteins leading to the unfolded protein response (UPR). Reactive oxygen species (ROS) such as superoxide and HO derived from NADPH oxidases have been implicated in the pathogenesis of cardiovascular diseases. ROS have also been associated with ER stress.

Durability of bioprostheses for the tricuspid valve in patients with congenital heart disease.

Objectives: Only little data exist on the durability of bioprostheses in the tricuspid position in patients with congenital heart disease (CHD). The aim of the study was to determine the reoperation rate and the valve function after primary implantation.

Methods: Between 1990 and 2013, 51 patients with CHD underwent tricuspid valve (TV) replacement with a bioprosthesis.

Higher programmatic volume in paediatric heart surgery is associated with better early outcomes.

Objective: Previous analyses have suggested an association between centre volume and in-hospital mortality, post-operative complications, and mortality in those patients who suffer from a complication. We sought to determine the nature of this association using a multicentre cohort.

Methods: All the patients, aged 18 years or younger, undergoing heart surgery at centres participating in the European Congenital Heart Surgeons Database (2003-2013) were included.

Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase.

Aims: Nitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8-tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling.

Calcium and ROS: A mutual interplay.

Calcium is an important second messenger involved in intra- and extracellular signaling cascades and plays an essential role in cell life and death decisions. The Ca(2+) signaling network works in many different ways to regulate cellular processes that function over a wide dynamic range due to the action of buffers, pumps and exchangers on the plasma membrane as well as in internal stores. Calcium signaling pathways interact with other cellular signaling systems such as reactive oxygen species (ROS).

Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair.

Reactive oxygen and nitrogen species (e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis.

Oxygen regulates molecular mechanisms of cancer progression and metastasis.

Oxygen is the basic molecule which supports life and it truly is "god's gift to life." Despite its immense importance, research on "oxygen biology" has never received the light of the day and has been limited to physiological and biochemical studies. It seems that in modern day biology, oxygen research is summarized in one word "hypoxia.

Inhibition of endothelial nitric oxyde synthase increases capillary formation via Rac1-dependent induction of hypoxia-inducible factor-1α and plasminogen activator inhibitor-1.

Disruption of endothelial homeostasis results in endothelial dysfunction, characterised by a dysbalance between nitric oxide (NO) and reactive oxygen species (ROS) levels often accompanied by a prothrombotic and proproliferative state. The serine protease thrombin not only is instrumental in formation of the fibrin clot, but also exerts direct effects on the vessel wall by activating proliferative and angiogenic responses. In endothelial cells, thrombin can induce NO as well as ROS levels.

The HIF1 target gene NOX2 promotes angiogenesis through urotensin-II.

Urotensin-II (U-II) has been considered as one of the most potent vasoactive peptides, although its physiological and pathophysiological role is still not finally resolved. Recent evidence suggests that it promotes angiogenic responses in endothelial cells, although the underlying signalling mechanisms are unclear. Reactive oxygen species derived from NADPH oxidases are major signalling molecules in the vasculature.

The unfolded protein response controls induction and activation of ADAM17/TACE by severe hypoxia and ER stress.

The family of ADAM (a disintegrin and metalloproteinase) proteins has been implicated in tumor initiation and progression. ADAM17/tumor necrosis factor-α (TNFα)-converting enzyme (TACE) has been initially recognized to release TNFα as well as its receptors (TNFRs) from the membrane. ADAM17, TNFα and TNFR have been found upregulated in cancer patients, although the underlying mechanisms remain largely unknown.

NOX4 mediates activation of FoxO3a and matrix metalloproteinase-2 expression by urotensin-II.

The vasoactive peptide urotensin-II (U-II) has been associated with vascular remodeling in different cardiovascular disorders. Although U-II can induce reactive oxygen species (ROS) by the NADPH oxidase NOX4 and stimulate smooth muscle cell (SMC) proliferation, the precise mechanisms linking U-II to vascular remodeling processes remain unclear. Forkhead Box O (FoxO) transcription factors have been associated with redox signaling and control of proliferation and apoptosis.

Ring-enforced right ventricle-to-pulmonary artery conduit in Norwood stage I reduces proximal conduit stenosis.

Background: An increasing number of surgeons prefer to place a conduit from the right ventricle to the pulmonary artery at the time of the Norwood stage I procedure. Proximal conduit stenoses have led us to modify this technique by using ring-enforced polytetrafluoroethylene conduits.

Methods: Angiograms of 24 patients with conventional conduits (CC) and 28 patients with ring-enforced conduits (RC) before partial bidirectional cavopulmonary anastomosis were analyzed.

Bidirectional cavopulmonary connection without additional pulmonary blood flow as an ideal staging for functional univentricular hearts.

Objective: Our institutional policy differs from others substantially, as we never leave any additional blood flow at the time of performing bidirectional cavopulmonary connection (BCPC). The aim was to evaluate the influence of this strategy on hemodynamics and pulmonary artery development.

Methods: Between 2001 and 2006 a total of 124 patients had completion to a total cavopulmonary connection (TCPC).

Urotensin-II in the lung: a matter for vascular remodelling and pulmonary hypertension?

Urotensin-II (UII) is an evolutionary conserved peptide which has been initially discovered in the urophysis of the fish goby regulating body fluid composition and vascular tone. Mammalian UII has gained increasing interest since it has been considered as an even more potent vasoconstrictor than endothelin-1, although its efficiency is greatly variable throughout species and vascular beds. More recently, it has been shown that UII, which mediates its action via binding to the G-protein coupled urotensin-II receptor, is not only involved in the regulation of the vascular tone but can also stimulate a variety of signaling cascades in different cells and organs in the body including generation of reactive oxygen species and nitric oxide, activation of MAP kinases, and modulation of gene expression.

Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells.

The oxygen sensitive alpha-subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1alpha by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1alpha mRNA in response to hypoxia in pulmonary artery smooth muscle cells.

A new treatment option for pulmonary valvar insufficiency: first experiences with implantation of a self-expanding stented valve without use of cardiopulmonary bypass.

Objective: Pulmonary regurgitation is the predominant problem in the long-term follow-up of tetralogy of Fallot (TOF) patients after primary repair. Apart from standard homograft implantation, a percutaneous valve delivery approach has been described recently. A right ventricular outflow tract (RVOT) diameter of greater than 22mm, however, precludes percutaneous valve delivery.

NOX2 and NOX4 mediate proliferative response in endothelial cells.

Increased levels of reactive oxygen species (ROS) contribute to many cardiovascular diseases. In neutrophils, ROS are generated by a NADPH oxidase containing p22phox and NOX2. NADPH oxidases are also major sources of vascular ROS.