Expression of a mutated cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to enhance proliferation within CF airways, and cells expressing a mutated CFTR have been shown to be less susceptible to apoptosis. Because the CFTR is expressed in the epithelial cells lining the gastrointestinal tract and all CF mouse models are characterized by gastrointestinal obstruction, we hypothesized that CFTR null mice would have increased epithelial cell proliferation and reduced apoptosis within the small intestine. The rate of intestinal epithelial cell migration from crypt to villus was increased in CFTR null mice relative to mice expressing the wild-type CFTR. This difference in migration could be explained by an increase in epithelial cell proliferation but not by a difference in apoptosis within the crypts of Lieberkühn. In addition, using two independent sets of CF cell lines, we found that epithelial cell susceptibility to apoptosis was unrelated to the presence of a functional CFTR. Thus increased proliferation but not alterations in apoptosis within epithelial cells might contribute to the pathophysiology of CF.
Cardiac fibroblasts, as the source of extracellular matrix for the left ventricle, subserve important functions to cardiac remodeling and fibrotic development following myocardial infarction or with pressure-overload cardiac hypertrophy. The fibroblast may be the target cell for angiotensin-converting enzyme inhibitors (ACEI) that are cardioprotective and reverse collagen deposition and remodeling but whose mechanisms of action remain controversial. Because we previously documented phenotypic differences between cardiac fibroblasts from the spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) left ventricle, the present study evaluated whether phenotypic differences also exist in the release of endogenous arachidonic acid metabolites or in the activation of phospholipase D, and the importance of observed differences to the formation of collagen and the mechanism of action of ACEI. The experimental design compared endogenous sources of arachidonic acid with exogenous prelabeling of cells. Angiotensin II stimulated greater arachidonic acid release than bradykinin, and WKY cells were more responsive than SHR. The major prostanoid formed by cardiac fibroblasts was prostaglandin I2 (PGI2), with more prostacyclin production by WKY cells than SHR cells both under nonstimulated conditions and in response to angiotensin II or bradykinin. Beraprost, a PGI2 analogue, was shown to decrease growth rate and DNA synthesis of fibroblasts and to inhibit mRNA expression for collagen types I and III, with SHR cells being less responsive to beraprost than WKY cells. These results potentially implicate eicosanoid metabolism, particularly PGI2, in collagen formation, fibrotic development, and cardiac remodeling, and they imply that the SHR genetic hypertension model may be predisposed to excess cardiac fibrosis.
Abstract-Cardiac fibrosis after myocardial infarction and in chronic hypertension involves an increase in the synthesis and deposition of collagen within the myocardium. Angiotensin-converting enzyme (ACE) inhibitors limit hypertrophy and fibrosis; their mechanism of action remains controversial, although kinins have been implicated to play a role. Because both bradykinin and prostaglandins (PG) have been shown to reduce collagen gene expression in cardiac fibroblasts, the goal of this study was to determine whether the bradykinin effect was mediated through enhanced prostaglandin formation by cardiac fibroblasts. Bradykinin increased [ 3 H]arachidonic acid metabolite release 2.3-fold over control and stimulated a dose-dependent increase in 6-keto PGF 1␣ (the stable metabolite of PGI 2 ) release from these cells, in which 1 nmol/L bradykinin produced a 4-fold increase in 6-keto PGF 1␣ release. Beraprost (a PGI 2 analogue) reduced steady-state pro␣1(I) and pro␣1(III) collagen mRNA levels by 35.6Ϯ6.6% and 34.2Ϯ10.0%, respectively. Bradykinininduced reductions in collagen type I and III gene expression were reversed by pretreatment with indomethacin. Our results indicate that one mechanism by which bradykinin modulates collagen biosynthesis via the rabbit cardiac fibroblast involves formation of arachidonic acid metabolites, particularly PGI 2 . The results of the present study argue that stabilization of endogenous kinins (as by ACE inhibitors) would enhance prostacyclin production and result in the attenuation of collagen gene expression, with potential implications for collagen synthesis and deposition within the myocardium. (Hypertension. 1998;32:84-88.) Key Words: bradykinin Ⅲ collagen Ⅲ prostaglandins Ⅲ fibroblasts Ⅲ rabbits A fter myocardial infarction and in chronic hypertension, the collagen content of the LV is increased. ACE inhibitors have been shown to be efficacious in the treatment of patients with these pathologies and to improve survival. [1][2][3] Furthermore, in animal studies, one consequence of the use of ACE inhibitors after coronary artery ligation or aortic banding is a reduction in LV hypertrophy 4,5 and collagen content of the myocardium. [6][7][8][9] This attenuation in collagen deposition and LV mass is blunted by coadministration of a BK receptor antagonist, 7,10,11 implying a role for the kinin system in regulating LV remodeling. Because ventricular remodeling involves both hypertrophic growth of myocytes and increases in interstitial fibrosis, ACE inhibitors potentially may alter either or both components. In recent studies from our laboratory and others, BK has been reported to reduce collagen gene expression via cardiac fibroblasts, 12,13 but the signaling pathways involved in BK-induced modulation of collagen expression have not been fully explored.Kinins stimulate the release of AA metabolites, including prostaglandins and prostanoids from a variety of cell types 14 -18 20 However, BK-induced stimulation of prostaglandin formation has not been fully examined as a primary mechan...
Cardiac fibroblasts, an abundant cell of the left ventricle (LV), proliferate and synthesize collagen in the heart after acute injury and during pressure overload hypertrophy. From many studies, angiotensin II (ANG II) receptors have been implicated in promoting collagen formation by the rat cardiac fibroblast. The present study examined species variability in ANG II receptor expression. Cultured rat fibroblasts expressed 43,000 ± 15,000 ANG II (AT1-specific) receptors per cell (dissociation constant = 0.92 ± 0.34 nM), whereas rabbit and neonate human cardiac fibroblast cultures expressed few receptors. Angiotensin increased intracellular Ca2+ concentration in rats but not in rabbit or human cardiac fibroblasts and stimulated arachidonic acid release in rat but not rabbit fibroblasts. In situ, 6 days after coronary artery ligation, angiotensin receptor expression was increased 34.8 ± 13.4-fold in the infarcted area relative to the noninfarcted tissue in the rat LV, whereas rabbit hearts demonstrated only a 3.2 ± 1.6-fold increase in ANG II binding within the infarcted tissue. These species differences in receptor expression raise questions as to the role of angiotensin as a mediator of collagen formation across species and as a direct target of angiotensin-converting enzyme inhibitors to regulate cardiac fibroblast function.
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