Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis

This work was supported by the British Lung Foundation. C.J.S. is supported by a Medical Research Council Fellowship

Multidrug resistance proteins preferentially regulate natriuretic peptide-driven cGMP signalling in the heart & vasculature.

BACKGROUND & PURPOSE: Cyclic-3',5'-guanosine monophosphate (cGMP) underpins the bioactivity of nitric oxide (NO) and natriuretic peptides and is key to cardiovascular homeostasis. Cyclic GMP-driven responses are terminated primarily by phosphodiesterases but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo. EXPERIMENTAL APPROACHES: Proliferation of human coronary artery smooth muscle cells (hCASMC), vasorelaxation of murine aorta and reductions in mean arterial blood pressure (MABP) in response to NO-donors or natriuretic peptides was determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced HF was also explored. KEY RESULTS: MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and ANP. MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP, but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental HF. These beneficial actions of MRP inhibition were associated with a greater intra:extra -cellular cGMP ratio in vitro and in vivo. CONCLUSIONS & IMPLICATIONS: MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity

NKX2-5 regulates vessel remodelling in scleroderma-associated pulmonary arterial hypertension.

NKX2-5 is a member of the homeobox-containing transcription factors critical in regulating tissue differentiation in development. Here, we report a role for NKX2-5 in vascular smooth muscle cell phenotypic modulation in vitro and in vascular remodelling in vivo. NKX2-5 is up-regulated in scleroderma (SSc) patients with pulmonary arterial hypertension. Suppression of NKX2-5 expression in smooth muscle cells, halted vascular smooth muscle proliferation and migration, enhanced contractility and blocked the expression of the extracellular matrix genes. Conversely, overexpression of NKX2-5 suppressed the expression of contractile genes (ACTA2, TAGLN, CNN1) and enhanced the expression of matrix genes (COL1) in vascular smooth muscle cells. In vivo, conditional deletion of NKX2-5 attenuated blood vessel remodelling and halted the progression to hypertension in the mouse chronic hypoxia mouse model. This study revealed that signals related to injury such as serum and low confluence, which induce NKX2-5 expression in cultured cells, is potentiated by TGFβ and further enhanced by hypoxia. The effect of TGFβ was sensitive to ERK5 and PI3K inhibition. Our data suggest a pivotal role for NKX2-5 in the phenotypic modulation of smooth muscle cells during pathological vascular remodelling and provide proof of concept for therapeutic targeting of NKX2-5 in vasculopathies

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial

This is the peer reviewed version of the following article: Hobbs AJ, Moyes AJ, Baliga RS, et al. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial. Br J Pharmacol. 2019. https://doi.org/10.1111/bph.14621, which has been published in final form at https://doi.org/10.1111/bph.14621. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThis work was supported by a British Heart Foundation Project Grant (PG/11/88/28992) and the National Institutes for Health Research, Comprehensive Biomedical Research Centre award to UC

Functional Locomotor Consequences of Uneven Forefeet for Trot Symmetry in Individual Riding Horses

ABSTRACT: Left-right symmetrical distal limb conformation can be an important prerequisite for a successful performance, and it is often hypothesized that asymmetric or uneven feet are important enhancing factors for the development of lameness. On a population level, it has been demonstrated that uneven footed horses are retiring earlier from elite level competition, but the biomechanical consequences are not yet known. The objectives of this study were to compare the functional locomotor asymmetries of horses with uneven to those with even feet. Hoof kinetics and distal limb kinematics were collected from horses (n = 34) at trot. Dorsal hoof wall angle was used to classify horses as even or uneven (1.5° difference between forefeet respectively) and individual feet as flat (55°). Functional kinetic parameters were compared between even and uneven forefeet using MANOVA followed by ANOVA. The relative influences of differences in hoof angle between the forefeet and of absolute hoof angle on functional parameters were analysed using multiple regression analysis (P<0.05). In horses with uneven feet, the side with the flatter foot showed a significantly larger maximal horizontal braking and vertical ground reaction force, a larger vertical fetlock displacement and a suppler fetlock spring. The foot with a steeper hoof angle was linearly correlated with an earlier braking-propulsion transition. The conformational differences between both forefeet were more important for loading characteristics than the individual foot conformation of each individual horse. The differences in vertical force and braking force between uneven forefeet could imply either an asymmetrical loading pattern without a pathological component or a subclinical lameness as a result of a pathological development in the steeper foot

C-type natriuretic peptide co-ordinates cardiac structure and function.

AIMS: C-type natriuretic peptide (CNP) is an essential endothelium-derived signalling species that governs vascular homoeostasis; CNP is also expressed in the heart but an intrinsic role for the peptide in cardiac function is not established. Herein, we employ unique transgenic strains with cell-specific deletion of CNP to define a central (patho)physiological capacity of CNP in maintaining heart morphology and contractility. METHODS AND RESULTS: Cardiac structure and function were explored in wild type (WT), cardiomyocyte (cmCNP-/-), endothelium (ecCNP-/-), and fibroblast (fbCNP-/-)-specific CNP knockout mice, and global natriuretic peptide receptor (NPR)-B-/-, and NPR-C-/- animals at baseline and in experimental models of myocardial infarction and heart failure (HF). Endothelium-specific deletion of CNP resulted in impaired coronary responsiveness to endothelium-dependent- and flow-mediated-dilatation; changes mirrored in NPR-C-/- mice. Ex vivo, global ischaemia resulted in larger infarcts and diminished functional recovery in cmCNP-/- and NPR-C-/-, but not ecCNP-/-, vs. WT. The cardiac phenotype of cmCNP-/-, fbCNP-/-, and NPR-C-/- (but not ecCNP-/- or NPR-B-/-) mice was more severe in pressure overload- and sympathetic hyperactivation-induced HF compared with WT; these adverse effects were rescued by pharmacological CNP administration in WT, but not NPR-C-/-, mice. At a molecular level, CNP/NPR-C signalling is impaired in human HF but attenuates activation of well-validated pro-hypertrophic and pro-fibrotic pathways. CONCLUSION: C-type natriuretic peptide of cardiomyocyte, endothelial and fibroblast origins co-ordinates and preserves cardiac structure, function, and coronary vasoreactivity via activation of NPR-C. Targeting NPR-C may prove an innovative approach to treating HF and ischaemic cardiovascular disorders.NHLBI Institute of the US National Institutes of Health [HL089847 and HL105993 to K.B.M.]

‘The only game in town?’: football match-fixing in Greece

The final publication is available at Springer via http://dx.doi.org/10.1007/s12117-014-9239-3Football match-fixing in Greece has a relatively long history, however, from the late 1990s it has been considered as a serious problem for the sport in the country. Despite the history of the phenomenon in the country, Greece has only relatively recently been identified as one of the hotspots for football match-fixing on an international level. Following the recent scandal exposure of fixed matches in Greece in 2011, also known as Koriopolis (a pun name on the Italian scandal Calciopolis and the Greek word ‘korios’ or phone-tap), detailed information about numerous matches played in the 2008/09, 2009/10 and 2010/11 seasons that attracted UEFA’s attention were brought into the public eye. Soon after, legal action was taken against individuals involved in the process, with a number of club officials facing lifelong bans from any footballrelated activity, and football clubs either relegated or excluded from European competitions and the Super League itself for their involvement in the scandal. In May 2013, the number of people facing charges exceeded 200, with some of them having already been imprisoned for their involvement in the scandal. Following the aforementioned scandal exposure, a vast amount of information regarding football match-fixing was made available to the public. The aim of the current article is to provide an account of the social organisation of football match-fixing in Greece. Our account is based on three main sources of data: the telephone conversations that were the result of wiretapping by the National Intelligence Agency in relation to the latest football match-fixing scandal (of 2011), published media sources, and interviews with informed actors from the realm of Greek football

Patient Access to U.S. Physicians Who Conduct Internet or E-mail Consults

BACKGROUND: E-mail communication has the potential to improve communication between patients and doctors. OBJECTIVE: The objective of the study is to describe the access of patients to physicians who conduct e-mail consults. METHODS: We analyzed data from the National Ambulatory Medical Care Survey (NAMCS), a nationally representative cross-sectional survey of office-based physician visits, in 2001, 2002, and 2003. The main outcome measure was the percentage of visits to a provider who reported doing internet or e-mail consults. RESULTS: There was fewer than 1 in 10 outpatient visits in 2001 (9.2%) to physicians who reported doing internet or e-mail consults, and this did not increase in 2002 (5.8%) or 2003 (5.5%). Access to these physicians was greater among patients who were male, nonminority, lived in the Western United States, seen for pre-/postoperative care, seen by a primary care provider, and not seen by a nurse during their visit. Access to physicians who conducted internet or e-mail consults was independent of other patient (e.g., chronic conditions), provider (e.g., office setting), and visit (e.g., medications prescribed) characteristics. CONCLUSIONS: Access to physicians who do internet or e-mail consults is generally low and did not increase between 2001 and 2003, despite growth in internet access and in other internet-related activities