Increased Expression of Connective Tissue Growth Factor in the Infarct Zone of Experimentally Induced Myocardial Infarction in Rats

Ohnishi, Hiromichi; Oka, Takefumi; Kusachi, Shozo; Nakanishi, Tohru; Takeda, Kenji; Nakahama, Makoto; Doi, Masayuki; Murakami, Takashi; Ninomiya, Yoshifumi; Takigawa, Masaharu; Tsuji, Takao

doi:10.1006/jmcc.1998.0799

Cited by 116 publications

(82 citation statements)

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“…Previous studies have shown that TGF-␤1, CTGF, and ET-1 increase in hypoxic tissue damages (29)(30)(31), and that their expression increases with aging (49,50) and diabetes (51)(52)(53). In the present study, we found that these three genes were more expressed in B1RB2R-null mice than B2R-null mice, and more expressed in B2R-null mice than WT, suggesting that both B1R and B2R are protective against renal cell damage in I/R injury.…”

Section: Discussionsupporting

confidence: 66%

See 1 more Smart Citation

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

Kakoki

McGarrah

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

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To explore the role of the kallikrein-kinin system in relation to ischemia/reperfusion injury in the kidney, we generated mice lacking both the bradykinin B1 and B2 receptor genes (B1RB2R-null, Bdkrb1 ؊/ ؊/Bdkrb2 ؊/؊ ) by deleting the genomic region encoding the two receptors. In 4-month-old mice, blood pressures were not significantly different among B1RB2R-null, B2R-null (Bdkrb2 ؊/؊ ), and WT mice. After 30 min of bilateral renal artery occlusion and 24 h of reperfusion, mortality rates, renal histological and functional changes, 8-hydroxy-2 -deoxyguanosine levels in total DNA, mtDNA deletions, and the number of TUNEL-positive cells in the kidneys increased progressively in the following order (from lowest to highest): WT, B2R-null, and B1RB2R-null mice. Increases in mRNA levels of TGF-␤1, connective tissue growth factor, and endothelin-1 after ischemia/reperfusion injury were also exaggerated in the same order (from lowest to highest): WT, B2R-null, and B1RB2R-null. Thus, both the B1 and B2 bradykinin receptors play an important role in reducing DNA damage, apoptosis, morphological and functional kidney changes, and mortality during renal ischemia/reperfusion injury.hypoxia ͉ mitochondria ͉ oxidative stress I schemic tissue injuries, including stroke, myocardial infarction, and ischemic acute renal failure, are devastating complications in patients with hypertension, diabetes, atherosclerosis, and senescence. In organ transplantation, damage to allografts during any ischemic period before the transplant markedly influences short-term and long-term graft function and outcome (1). Furthermore, although reoxygenation after ischemia is essential for cell survival, damage also develops during the reperfusion period. Previous studies have shown that acute ATP depletion, intracellular Ca 2ϩ accumulation, and increased generation of reactive oxygen species by mitochondria all play important roles in the pathogenesis of ischemia/reperfusion (I/R) injury (2).Angiotensin-I-converting enzyme (ACE) inhibitors (ACEIs) reduce not only chronic cardiovascular remodeling after ischemia but also acute tissue injury caused by I/R in the heart (3), lung (4), liver (5), and kidneys (6, 7). Several observations indicate that the beneficial effects of ACEIs in the acute phase are mainly due to activation of the bradykinin nitric oxide (NO) cascade as a result of inhibition of the inactivation of bradykinin, rather than due to suppression of angiotensin II formation. Thus, ACEIs are much more effective than angiotensin type I receptor antagonists in protecting against I/R (8-10), and bradykinin B2 receptor (B2R) antagonists and NO synthase blockers markedly attenuate the protective effects of ACEIs (8, 9, 11).Bradykinin and lysyl-bradykinin (kallidin) are generated from kininogens by the kallikreins and some other serine proteases. ACE, which is a carboxydipeptidase, inactivates both peptides by removing two amino acids from their carboxyl termini. In mammals, at least two receptors have been identified: the bradykinin B1 receptor (B...

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Section: Discussionsupporting

confidence: 66%

“…The mRNA levels of TGF-␤1 (29), connective tissue growth factor (CTGF) (30), and endothelin (ET)-1 (31) were increased in I/R injury, and these increases were greater in B1RB2R-null than in B2R-null mice and more in B2R-null than in WT mice (Fig. 7 E-G).…”

Section: Resultsmentioning

confidence: 99%

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

Kakoki

McGarrah

Kim

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

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“…In the present study we show that an experimental increase in plasma lipids increases CTGF mRNA and protein expression, so we can now include increased plasma FFA concentrations as one of the potential regulators of CTGF expression. There is evidence that CTGF mediates fibrotic changes in atherosclerotic plaques (37), mesangial expansion in models of diabetic nephropathy (38,39), fibrosis induced by cardiac myofibroblasts following myocardial infarction (40), and scleroderma and keloids (41). Of note, CTGF expression is increased in liver from Zucker obese rats in association with lipid abnormalities and fatty liver in this animal model of insulin resistance (36).…”

Section: Subjectmentioning

confidence: 79%

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

Richardson

Kashyap

Bajaj

et al. 2005

Journal of Biological Chemistry

226

200

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The association between elevated plasma free fatty acid (FFA) concentrations and insulin resistance is well known. Although the cause and effect relationship between FFAs and insulin resistance is complex, plasma FFA is negatively correlated with the expression of peroxisome proliferator activated receptor-␥ cofactor-1 (PGC-1) and nuclear encoded mitochondrial genes. To test whether this association is causal, we infused a triglyceride emulsion (or saline as control) into healthy subjects to increase plasma FFA for 48 h followed by muscle biopsies, microarray analysis, quantitative real time PCR, and immunoblots. Lipid infusion increased plasma FFA concentration from 0.48 ؎ 0.02 to 1.73 ؎ 0.43 mM and decreased insulin-stimulated glucose disposal from 8.82 ؎ 0.69 to 6.67 ؎ 0.66 mg/kg⅐min, both with p < 0.05. PGC-1 mRNA, along with mRNAs for a number of nuclear encoded mitochondrial genes, were reduced by lipid infusion (p < 0.05). Microarray analysis also revealed that lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA expression of collagens and multiple extracellular matrix genes was higher after the lipid infusion (p < 0.05). Immunoblot analysis revealed that lipid infusion also increased the expression of collagens and the connective tissue growth factor protein. These data suggest that an experimental increase in FFAs decreases the expression of PGC-1 and nuclear encoded mitochondrial genes and also increases the expression of extracellular matrix genes in a manner reminiscent of inflammation.

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“…This statement notwithstanding, we cannot exclude a potential contributory role for Smad independent pro-fibrotic mechanisms, including activation of extracellular signal-regulated kinase, 30 the Rho/Rho-kinase signaling pathway, 31 and connective tissue growth factor. 32,33 Although TGF-β mediated signaling has been shown to be important in myocardial fibrosis, it is worth noting a recent study in transgenic mice with cardiac restricted overexpression of a constitutively active TGF-β 1 mutant, which showed that the expression of this constitutively active mutant did lead to the development of ventricular fibrosis. 34 Moreover, fibrosis was not observed in hearts engrafted with skeletal myoblasts expressing high levels of TGF-β 1 .…”

Section: Tgf-β Signaling and Myocardial Fibrosismentioning

confidence: 99%

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Sakata¹,

Chancey²,

Divakaran³

et al. 2007

Basic Res Cardiol

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The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a proinflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase levels transforming growth factor-β (TGF-β) mRNA and protein. In order to determine whether TGF-β mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study myocardial collagen content was determined using the picrosirius red technique, and LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness in the MHCsTNF mice when compared to diluent treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.

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Increased Expression of Connective Tissue Growth Factor in the Infarct Zone of Experimentally Induced Myocardial Infarction in Rats

Cited by 116 publications

References 0 publications

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

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