C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis

Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) fulfills a multimodal protective role in the cardiovascular system governing local blood flow, angiogenesis, cardiac function, and immune cell reactivity. Herein, we investigated a parallel, preservative function for CNP in coordinating metabolic homeostasis. Global inducible CNP knockout mice exhibited reduced body weight, higher temperature, lower adiposity, and greater energy expenditure in vivo. This thermogenic phenotype was associated with increased expression of uncoupling protein-1 and preferential lipid utilization by mitochondria, a switch corroborated by a corresponding diminution of insulin secretion and glucose clearance. Complementary studies in isolated murine and human adipocytes revealed that CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via G(i)-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-γ coactivator-1α expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G. Finally, we identified an association between CNP/NPR-C expression and obesity in patient samples. These findings establish a pivotal physiological role for CNP as a metabolic switch to balance energy homeostasis. Pharmacological targeting of these receptors may offer therapeutic utility in the metabolic syndrome and related cardiovascular disorders

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

Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC

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.]

Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)

Control of disseminated intravascular coagulation in Klippel-Trenaunay-Weber syndrome using enoxaparin and recombinant activated factor VIIa: a case report

<p>Abstract</p> <p>Introduction</p> <p>Vascular malformation is associated with coagulopathies, especially when hemostasis is challenged.</p> <p>Case presentation</p> <p>We present the case of an 11-year-old Hispanic girl with Klippel-Trenaunay-Weber syndrome that developed disseminated intravascular coagulation after minor surgery, which was controlled by blood product transfusions and enoxaparin to address an ongoing consumptive coagulopathy. The patient, however, developed bacteremia and liver trauma that resulted in severe bleeding. To the best of our knowledge, we report here the first known instance of administering recombinant coagulation factor VIIa to control acute bleeding in a patient with Klippel-Trenaunay-Weber syndrome.</p> <p>Conclusions</p> <p>This case illustrates the concept of enoxaparin maintenance to suppress an ongoing consumptive coagulopathy and the use of recombinant coagulation factor VIIa to control its potentially fatal severe bleeding episodes.</p

Endothelial C-Type Natriuretic Peptide is a Critical Regulator of Angiogenesis and Vascular Remodeling.

BACKGROUND: Angiogenesis and vascular remodeling are complementary, innate responses to ischemic cardiovascular events, including peripheral artery disease (PAD) and myocardial infarction, which restore tissue blood supply and oxygenation; the endothelium plays a critical function in these intrinsic protective processes. C-type natriuretic peptide (CNP) is a fundamental endothelial signaling species that coordinates vascular homeostasis. Herein, we sought to delineate a central role for CNP in angiogenesis and vascular remodeling in response to ischemia. METHODS: The in vitro angiogenic capacity of CNP was examined in pulmonary microvascular endothelial cells (PMEC) and aortic rings isolated from wild type (WT), endothelium-specific CNP knockout (ecCNP-/-), and global natriuretic peptide receptor (NPR)-B-/- and NPR-C-/- animals, and in human umbilical vein endothelial cells (HUVEC). These studies were complemented by in vivo investigation of neovascularization and vascular remodeling following ischemia or vessel injury, and CNP/NPR-C expression & localization in tissue from patients with PAD. RESULTS: Clinical vascular ischemia is associated with reduced levels of CNP and its cognate NPR-C. Moreover, genetic or pharmacological inhibition of CNP and NPR-C, but not NPR-B, reduces the angiogenic potential of PMEC, HUVEC and isolated vessels ex vivo. Angiogenesis and remodeling are impaired in vivo in ecCNP-/- and NPR-C-/-, but not NPR-B-/-, mice; the detrimental phenotype caused by genetic deletion of endothelial CNP, but not NPR-C, can be rescued by pharmacological administration of CNP. The pro-angiogenic effect of CNP/NPR-C is dependent on activation of Gi, ERK1/2 and PI3Kγ/Akt at a molecular level. CONCLUSIONS: These data define a central (patho)physiological role for CNP in angiogenesis and vascular remodeling in response to ischemia and provide the rationale for pharmacological activation of NPR-C as an innovative approach to treating PAD and ischemic cardiovascular disorders

Barriers to apply cardiovascular prediction rules in primary care: a postal survey

BACKGROUND: Although cardiovascular prediction rules are recommended by guidelines to evaluate global cardiovascular risk for primary prevention, they are rarely used in primary care. Little is known about barriers for application. The objective of this study was to evaluate barriers impeding the application of cardiovascular prediction rules in primary prevention. METHODS: We performed a postal survey among general physicians in two Swiss Cantons by a purpose designed questionnaire. RESULTS: 356 of 772 dispatched questionnaires were returned (response rate 49.3%). About three quarters (74%) of general physicians rarely or never use cardiovascular prediction rules. Most often stated barriers to apply prediction rules among rarely- or never-users are doubts concerning over-simplification of risk assessment using these instruments (58%) and potential risk of (medical) over-treatment (54%). 57% report that the numerical information resulting from prediction rules is often not helpful for decision-making in practice. CONCLUSION: If regular application of cardiovascular prediction rules in primary care is in demand additional interventions are needed to increase acceptance of these tools for patient management among general physicians

Divergent mind-sets, convergent policies: Policing models against organized crime in Italy and in England within international frameworks

The fight against organized crime is a very fertile ground for policymaking at various levels. On one side, because of the perceived transnationality of the phenomenon, national states are inclined to develop harmonized responses within the European or international law frameworks. On the other side, national conceptualizations and manifestations of organized crime often make these harmonizations quite challenging. This paper shares the findings of a socio-legal investigation carried out in England and in Italy through interviews and document analysis, comparing the two national models against organized crime. The paper presents these two models ? the Italian Structure Model and the English Activity Model, which are very different in many ways ? in order to identify divergences and convergences of policies and practices. This comparative exercise not only improves our understanding of national approaches, beyond cultural, linguistic and legal boundaries, but also improves the dialogue towards concerted efforts at the international level. Nevertheless, the globalization of criminal markets and the internationalization of policies have influenced perceptions of organized crime and related policing tactics at national levels too. This paper will briefly look at international perspectives to assess to what extent divergent and convergent areas between the two models are also areas of interest and focus at the international level, in order to conclude with an enhanced understanding of both models before drawing conclusions

Atlanto-axial rotatory fixation in a girl with Spondylocarpotarsal synostosis syndrome

We report a 15-year-old girl who presented with spinal malsegmentation, associated with other skeletal anomalies. The spinal malsegmentation was subsequently discovered to be part of the spondylocarpotarsal synostosis syndrome. In addition, a distinctive craniocervical malformation was identified, which included atlanto-axial rotatory fixation. The clinical and the radiographic findings are described, and we emphasise the importance of computerised tomography to characterize the craniocervical malformation complex. To the best of our knowledge, this is the first clinical report of a child with spondylocarpotarsal synostosis associated with atlanto-axial rotatory fixation