Regulation of Ncx1 Expression Xu, Lin; Renaud, Ludivine; Müller, Joachim G. ...
The Journal of biological chemistry,
11/2006, Letnik:
281, Številka:
45
Journal Article
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The Na+-Ca2+ exchanger (NCX1) is up-regulated in hypertrophy and is often found up-regulated in end-stage heart failure. Studies have shown that the change in its expression contributes to ...contractile dysfunction. We have previously shown that the 1831-bp Ncx1 H1 (1831Ncx1) promoter directs cardiac-specific expression of the exchanger in both development and in the adult, and is sufficient for the up-regulation of Ncx1 in response to pressure overload. Here, we utilized adenoviral mediated gene transfer and transgenics to identify minimal regions and response elements that mediate Ncx1 expression in the heart. We demonstrate that the proximal 184 bp of the Ncx1 H1 (184Ncx1) promoter is sufficient for expression of reporter genes in adult cardiomyocytes and for the correct spatiotemporal pattern of Ncx1 expression in development but not for up-regulation in response to pressure overload. Mutational analysis revealed that both the -80 CArG and the -50 GATA elements were required for expression in isolated adult cardiomyocytes. Chromatin immunoprecipitation assays in adult cardiocytes demonstrate that SRF and GATA4 are associated with the proximal region of the endogenous Ncx1 promoter. Transgenic lines were established for the 1831Ncx1 promoter-luciferase containing mutations in the -80 CArG or -50 GATA element. No luciferase activity was detected during development, in the adult, or after pressure overload in any of the -80 CArG transgenic lines. The Ncx1 -50 GATA mutant promoter was sufficient for driving the normal spatiotemporal pattern of Ncx1 expression in development and for up-regulation in response to pressure overload but importantly, expression was no longer cardiac restricted. This work is the first in vivo study that demonstrates which cis elements are important for Ncx1 regulation.
The adhesion receptor beta3 integrin regulates diverse cellular functions in various tissues. As beta3 integrin has been implicated in extracellular matrix (ECM) remodeling, we sought to explore the ...role of beta3 integrin in cardiac fibrosis by using wild type (WT) and beta3 integrin null (beta3-/-) mice for in vivo pressure overload (PO) and in vitro primary cardiac fibroblast phenotypic studies. Compared to WT mice, beta3-/- mice upon pressure overload hypertrophy for 4 wk by transverse aortic constriction (TAC) showed a substantially reduced accumulation of interstitial fibronectin and collagen. Moreover, pressure overloaded LV from beta3-/- mice exhibited reduced levels of both fibroblast proliferation and fibroblast-specific protein-1 (FSP1) expression in early time points of PO. To test if the observed impairment of ECM accumulation in beta3-/- mice was due to compromised cardiac fibroblast function, we analyzed primary cardiac fibroblasts from WT and beta3-/- mice for adhesion to ECM proteins, cell spreading, proliferation, and migration in response to platelet derived growth factor-BB (PDGF, a growth factor known to promote fibrosis) stimulation. Our results showed that beta3-/- cardiac fibroblasts exhibited a significant reduction in cell-matrix adhesion, cell spreading, proliferation and migration. In addition, the activation of PDGF receptor associated tyrosine kinase and non-receptor tyrosine kinase Pyk2, upon PDGF stimulation were impaired in beta3-/- cells. Adenoviral expression of a dominant negative form of Pyk2 (Y402F) resulted in reduced accumulation of fibronectin. These results indicate that beta3 integrin-mediated Pyk2 signaling in cardiac fibroblasts plays a critical role in PO-induced cardiac fibrosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
On February 28, 2004, a group of investigators and clinician scientists with expertise in the field of heart failure met for 2 days in Woodstock, VT, to discuss the status of the current heart ...failure nomenclature and to seek a consensus on whether and how this nomenclature might be changed. Despite a wide diversity of expressed opinions, several areas of discussion ultimately led to the consensus expressed in this document.
...I join Dr. Kessler in his enthusiastic use of the term "diastolic heart failure" and renew my editorial plea: "Stop the discrimination against the term diastolic heart failure."
Randomized Controlled Trial of an Implantable Continuous Hemodynamic Monitor in Patients With Advanced Heart Failure: The COMPASS-HF Study Robert C. Bourge, William T. Abraham, Philip B. Adamson, ...Mark F. Aaron, Juan M. Aranda, Anthony Magalski, Michael R. Zile, Andrew L. Smith, Frank W. Smart, Mark A. O’Shaughnessy, Mariell L. Jessup, Brandon Sparks, David L. Naftel, Lynne Warner Stevenson, on behalf of the COMPASS-HF Study Group The COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) study was a prospective, multicenter, randomized, single-blind, parallel-controlled trial of 274 New York Heart Association functional class III or IV heart failure (HF) patients who received an implantable continuous hemodynamic monitor. Patients were randomized to a Chronicle (Medtronic Inc., Minneapolis, Minnesota) (n = 134) or control (n = 140) group. The hemodynamic information from the device was used to guide patient management only in the Chronicle group. Compared with control patients, the Chronicle group had a nonsignificant 21% reduction (p = 0.33) in the rate of all HF-related events and a 36% reduction (p = 0.03) in the relative risk of a first HF-related hospitalization. Additional trials will be necessary to establish the clinical benefit of implantable continuous hemodynamic monitor–guided care in patients with advanced HF.
Measurements of diastolic function To fully characterize diastolic function, measurement of LV pressure, volume, wall thickness, and calculations that reflect the process of active relaxation (the ...rate of isovolumic LV pressure and LV filling) and those that reflect passive stiffness (chamber compliance and myocardial viscoelastic stiffness) must be made (2). Because this requires invasive methods and detailed analysis, these methods are difficult to use in patient screening or to perform in large clinical trials. ...recent studies have shown that it may not be necessary to directly measure diastolic function in every patient to prove that they have HF caused by a predominant abnormality in diastolic function (3). ...the absence of a simple, noninvasive, load-independent measure of diastolic dysfunction does not justify avoiding an assessment of diastolic function when necessary, nor does it justify the use the more descriptive terminology "HF with a preserved EF."
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