Connective tissue growth factor (CTGF) is a cysteine-rich peptide synthesized and secreted by fibroblastic cells after activation with transforming growth factor beta (TGF-beta) that acts as a downstream mediator of TGF-beta-induced fibroblast proliferation. We performed in vitro and in vivo studies to determine whether CTGF is also essential for TGF-beta-induced fibroblast collagen synthesis. In vitro studies with normal rat kidney (NRK) fibroblasts demonstrated CTGF potently induces collagen synthesis and transfection with an antisense CTGF gene blocked TGF-beta stimulated collagen synthesis. Moreover, TGF-beta-induced collagen synthesis in both NRK and human foreskin fibroblasts was effectively blocked with specific anti-CTGF antibodies and by suppressing TGF-beta-induced CTGF gene expression by elevating intracellular cAMP levels with either membrane-permeable 8-Br-cAMP or an adenylyl cyclase activator, cholera toxin (CTX). cAMP also inhibited collagen synthesis induced by CTGF itself, in contrast to its previously reported lack of effect on CTGF-induced DNA synthesis. In animal assays, CTX injected intradermally in transgenic mice suppressed TGF-beta activation of a human CTGF promoter/lacZ reporter transgene. Both 8-Br-cAMP and CTX blocked TGF-beta-induced collagen deposition in a wound chamber model of fibrosis in rats. CTX also reduced dermal granulation tissue fibroblast population increases induced by TGF-beta in neonatal mice, but not increases induced by CTGF or TGF-beta combined with CTGF. Our data indicate that CTGF mediates TGF-beta-induced fibroblast collagen synthesis and that in vivo blockade of CTGF synthesis or action reduces TGF-beta-induced granulation tissue formation by inhibiting both collagen synthesis and fibroblast accumulation.
Relaxin is a reproductive hormone that has historically been characterized as being responsible for pubic ligament loosening and cervical ripening. Recently, relaxin has been associated with neovascularization of the endometrial lining of the uterus, potentially via specific induction of vascular endothelial growth factor. Previously conducted clinical studies using partially purified porcine relaxin have described relaxin's ability to stimulate the healing of ischemic wounds, suggesting that relaxin may also have angiogenic effects at sites of ischemic wound healing. In the present study, relaxin's angiogenic effects in the context of wound repair were tested in rodent models of angiogenesis and wound healing. Relaxin showed an ability to stimulate new blood vessel formation, particularly at ischemic wound sites, and to induce both vascular endothelial growth factor and basic fibroblast growth factor specifically in cells, presumably including macrophages, collected from wound sites. Resident macrophages collected from nonwound sites, such as the lung, did not show altered expression of these cytokines following relaxin administration. Because angiogenic wound cells are frequently macrophages, THP-1 cells, a cell line of monocyte lineage that binds relaxin specifically, were tested for and shown to induce vascular endothelial growth factor and basic fibroblast growth factor in response to relaxin. In conclusion, relaxin may be useful in the treatment of ischemic wounds by stimulating angiogenesis via the induction of vascular endothelial growth factor and basic fibroblast growth factor in wound macrophages.
To assess whether chronic ouabain administration causes hypertension by increasing sympathetic activity, we recorded arterial blood pressure and heart rate at rest and after ganglionic blockade in conscious Wistar rats following 10 to 14 days of central or peripheral administration of ouabain. Intracerebroventricular or intravenous infusion of ouabain (10 fig/d for both) as well as subcutaneous ouabain pellets (releasing 25 fig ouabain/d per pellet) increased mean arterial pressure by 20 to 30 mm Hg and heart rate by 40 to 60 beats per minute. Ouabain pellets increased blood pressure and heart rate in a dose-related manner. After 2 weeks of all ouabain treatments, ouabainlike activity in plasma was not changed but increased significantly in hypothalamus and adrenals. Ouabainlike activity in the adrenals was increased more T he relation between high sodium intake and hypertension in salt-sensitive hypertensive rats is complex and not yet understood. We have postulated that high sodium intake intermittently increases Na + concentrations in the cerebrospinal fluid, inducing increased central levels of ouabainlike activity (OLA) and thereby an increase in sympathetic outflow and blood pressure (BP).1 ' 2 Substances with OLA are present peripherally and centrally in both normotensive and hypertensive humans and animals 2 -4 and may be of central origin.2 -4 Brain OLA content is higher in spontaneously hypertensive rats (SHR) than Wistar-Kyoto (WKY) rats, and high sodium intake further increases brain OLA in SHR. 4 Augmented sympathetic activity has been documented in several forms of sodiumdependent hypertension, including Dahl salt-sensitive (DS) rats 5 and SHR. 6 Brain OLA may play a primary role in mediating the sympathoexcitatory and hypertensive effects of high sodium intake in SHR 7 and DS rats. In humans, circulating OLA is indistinguishable from the glycoside ouabain in terms of biochemical structure and several physiological effects.3 Furthermore, receptors for ouabain in, for instance, arterial smooth muscle cells 9 and the central nervous system 10 appear to be identical to those for OLA. If an increase in brain or peripheral OLA contributes to the development of hypertension in sodium-sensitive rats, chronic administration of exogenous ouabain should induce hypertension in normotensive rats as well. In normotensive rats, From the Hypertension Unit, University of Ottawa (Ontario, Canada) Heart Institute.Correspondence to Frans H.H. Leenen, MD, PhD, FRCPC, Hypertension Unit, Room H360, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, Canada K1Y 4E9. by intravenous than subcutaneous or intracerebroventricular ouabain treatment, but the different treatment modes caused similar increases in the hypothalamus. Concomitant central infusion of antibody Fab fragments against ouabain prevented the ouabain pellet-induced increases in blood pressure and heart rate. Ganglionic blockade by intravenous hexamethonium normalized blood pressure and heart rate in ouabaintreated rats. These data s...
Background-Left ventricular (LV) remodeling after myocardial infarction (MI) is associated with fibrosis, dilatation, and dysfunction. We postulated that prevention of fibrosis after MI with a prolyl 4-hydroxylase inhibitor (P4HI) would preserve LV function and attenuate LV enlargement. Methods and Results-Adult female rats (200 to 250 g) had experimental MI and were then randomized to treatment with P4HI (MI-FG041, nϭ29) or vehicle (MI-control, nϭ29) 48 hours after MI for 4 weeks in 2 phases. Echocardiograms were performed weekly with a 15-MHz linear transducer, and at 4 weeks, collagen isoform determinations and in vivo hemodynamics were performed. At randomization, the infarct size and LV function and size were similar in MI-FG041 and MI-control but significantly different from shams (nϭ9). At week 4, the LV function in MI-FG041 was significantly better than in MI-controls (fractional shortening 21% versus 16%, Pϭ0.01; fractional area change 30% versus 19%, Pϭ0.002; ejection fraction 35% versus 23%, Pϭ0.001). In the FG041 group, LV area in systole was less (PϽ0.05), the dP/dt max after isoproterenol was higher (PϽ0.05), and types I and III collagen in noninfarcted LV were less than in MI-control. The hydroxyproline/proline ratio was increased by 64% in MI-control and reduced to the sham value in MI-FG041 rats. In the scar tissue, it was reduced by 24% in MI-FG041. Conclusions-This
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