prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin.
Background-Angiotensin-converting enzyme (ACE) inhibitors are valuable agents for the treatment of hypertension, heart failure, and other cardiovascular and renal diseases. The cardioprotective effects of ACE inhibitors are mediated by blockade of both conversion of angiotensin (Ang) I to Ang II and kinin hydrolysis. Here, we report a novel mechanism that may explain the cardiac antifibrotic effect of ACE inhibition, involving blockade of the hydrolysis of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Methods and Results-To study the role of Ac-SDKP in the therapeutic effects of the ACE inhibitor captopril, we used a model of Ang II-induced hypertension in rats treated with the ACE inhibitor either alone or combined with a blocking monoclonal antibody (mAb) to Ac-SDKP. These hypertensive rats had left ventricular hypertrophy (LVH) as well as increases in cardiac fibrosis, cell proliferation, transforming growth factor- (TGF-) expression, and phosphorylation of Smad2 (P-Smad2), a signaling mediator of the effects of TGF-. The ACE inhibitor did not decrease either blood pressure or LVH; however, it significantly decreased LV collagen from 13.3Ϯ0.9 to 9.6Ϯ0.6 g/mg dry wt (PϽ0.006), and this effect was blocked by the mAb (12.1Ϯ0.6; PϽ0.034, ACE inhibitor versus ACE inhibitorϩmAb). In addition, analysis of interstitial collagen volume fraction and perivascular collagen (picrosirius red staining) showed a very similar tendency. Likewise, the ACE inhibitor significantly decreased LV monocyte/macrophage infiltration, cell proliferation, and TGF- expression, and these effects were blocked by the mAb. Ang II increased Smad2 phosphorylation 3.2Ϯ0.9-fold; the ACE inhibitor lowered this to 0.6Ϯ0.1-fold (PϽ0.001), and the mAb blocked this decrease to 2.1Ϯ0.3 (PϽ0.001, ACE inhibitor versus ACE inhibitorϩmAb). Similar findings were seen when the ACE inhibitor was replaced by Ac-SDKP. Conclusions-We concluded that in Ang II-induced hypertension, the cardiac antifibrotic effect of ACE inhibitors is a result of the inhibition of Ac-SDKP hydrolysis, resulting in a decrease in cardiac cell proliferation (probably fibroblasts), inflammatory cell infiltration, TGF- expression, Smad2 activation, and collagen deposition.
Abstract-Angiotensin II (Ang II)-induced hypertension is associated with an inflammatory response that may contribute to the development of target organ damage. We tested the hypothesis that, in Ang II-induced hypertension, CC chemokine receptor 2 (CCR2) activation plays an important role in the development of renal fibrosis, damage, and dysfunction by causing oxidative stress, macrophage infiltration, and cell proliferation. To test this hypothesis, we used CCR2 knockout mice (CCR2 Ϫ/Ϫ ). The natural ligand of CCR2 is monocyte chemoattractant protein-1, a chemokine important for macrophage recruitment and activation. CCR2Ϫ/Ϫ and age-matched wild-type (CCR2 ϩ/ϩ ) C57BL/6J mice were infused continuously with either Ang II (5.2 ng/10 g per minute) or vehicle via osmotic minipumps for 2 or 4 weeks. Ang II infusion caused similar increases in systolic blood pressure and left ventricular hypertrophy in both strains of mice. However, in CCR2Ϫ/Ϫ mice with Ang II-induced hypertension, oxidative stress, macrophage infiltration, albuminuria, and renal damage were significantly decreased, and glomerular filtration rate was significantly higher than in CCR2 ϩ/ϩ mice. We concluded that, in Ang II-induced hypertension, CCR2 activation plays an important role in the development of hypertensive nephropathy via increased oxidative stress and inflammation. Key Words: inflammation Ⅲ chemokine receptors Ⅲ macrophage Ⅲ reactive oxygen species Ⅲ kidney diseases Ⅲ albuminuria Ⅲ fibrosis H ypertension is a major risk factor for renal nephrosclerosis; however, the mechanisms by which high blood pressure causes renal damage are not completely understood. Angiotensin II (Ang II), in addition to causing vasoconstriction, aldosterone release, and Na reabsorption by the nephron, also causes oxidative stress, inflammation, cell proliferation, and, as a consequence, interstitial matrix accumulation and target organ damage. In the kidney, Ang II causes renal inflammation by stimulating superoxide formation and increasing chemokine release. [1][2][3] Chemokines are a family of low-molecular-weight cytokines that induce activation and migration of inflammatory cells and modulate functions of these cells. Monocyte chemoattractant protein (MCP-1) is one of the most prominent chemokines that regulates monocyte-macrophage infiltration. MCP-1 acts via its receptor, the CC chemokine receptor 2 (CCR2). 4,5 In mice lacking CCR2 (CCR2 Ϫ/Ϫ ), Ang II-induced vascular inflammation and remodeling are significantly reduced. 6 In a unilateral ureteral obstruction model of renal fibrosis and inflammation, CCR2 blockade ameliorates fibrosis and macrophage infiltration. 7,8 Although these studies suggest that MCP-1/CCR2 activation, via macrophage infiltration, plays a crucial role in the development of vascular and renal damage, it is unknown whether it contributes to renal damage and dysfunction in hypertension. Here we test the hypothesis that, in Ang II-induced hypertension, CCR2 activation plays an important role in the development of renal fibrosis, damage, a...
Abstract-There is convincing evidence that chronic treatment with N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a peptide normally found in tissues and biological fluids, reduces collagen deposition in the heart and kidneys of hypertensive rats and rats with myocardial infarction. However, it is not known whether endogenous Ac-SDKP at basal concentrations has any physiological function related to collagen deposition. Prolyl oligopeptidase is responsible for release of Ac-SDKP from its precursor thymosin- 4 . When we treated rats with a specific oral rolyl oligopeptidase inhibitor, Ac-SDKP decreased significantly in the plasma, heart, and kidney. In the present study, we tested the hypothesis that endogenous Ac-SDKP at basal levels plays a physiological role, antagonizing and/or preventing excessive collagen deposition. We studied whether chronic blockade of Ac-SDKP promotes collagen accumulation and/or accelerates this process in the presence of a profibrotic stimulus such as angiotensin II. We found that decreased basal levels of Ac-SDKP increased cardiac and renal perivascular fibrosis and promoted glomerulosclerosis. Moreover, in the presence of angiotensin II decreasing basal levels of Ac-SDKP accelerated interstitial cardiac fibrosis attributable to an increase in cells that produce collagen. We concluded that Ac-SDKP participates in the regulation of collagen content under normal conditions. We believe this is the first study showing that this peptide plays a physiological role at basal concentrations, preventing organ collagen accumulation.
. Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 289: H2616-H2623, 2005. First published July 29, 2005 doi:10.1152/ajpheart.00546.2005.-Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS Ϫ/Ϫ ), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by N -nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS Ϫ/Ϫ mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MIϩvehicle, and MIϩL-NAME (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS Ϫ/Ϫ compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS Ϫ/Ϫ mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.
Angiotensin II (ANG II) contributes to hypertension, cardiac hypertrophy, fibrosis, and dysfunction; however, it is difficult to separate the cardiac effect of ANG II from its hemodynamic action in vivo. To overcome the limitations, we used transgenic mice with cardiac-specific expression of a transgene fusion protein that releases ANG II from cardiomyocytes (Tg-ANG II) and treated them with deoxycorticosterone acetate (DOCA)-salt to suppress their systemic renin-angiotensin system. Using this unique model, we tested the hypothesis that cardiac ANG II, acting on the angiotensin type 1 receptor (AT(1)R), increases inflammation, oxidative stress, and apoptosis, accelerating cardiac hypertrophy and fibrosis. Male Tg-ANG II mice and their nontransgenic littermates (n-Tg) were uninephrectomized and divided into the following three groups: 1) vehicle-treated normotensive controls; 2) DOCA-salt; and 3) DOCA-salt + valsartan (AT(1)R blocker).Under basal conditions, systolic blood pressure (SBP) and cardiac phenotypes were similar between strains. In DOCA-salt hypertension, SBP increased similarly in both n-Tg and Tg-ANG II, and cardiac function did not differ between strains; however, Tg-ANG II had 1) greater ventricular hypertrophy as well as interstitial and perivascular fibrosis; 2) a higher number of deoxynucleotidyl-transferase-mediated dUTP nick end labeling-positive cells and infiltrating macrophages; 3) increased protein expression of NADPH oxidase 2 and transforming growth factor-β(1); and 4) downregulation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (Akt) phosphorylation. Valsartan partially reversed these effects in Tg-ANG II but not in n-Tg. We conclude that, when hemodynamic loading conditions remain unchanged, cardiac ANG II does not alter heart size or cardiac functions. However, in animals with hypertension, cardiac ANG II, acting via AT(1)R, enhances inflammation, oxidative stress, and cell death (most likely via downregulation of PI 3-kinase and Akt), contributing to cardiac hypertrophy and fibrosis.
Abstract-Angiotensin-converting enzyme inhibitors (ACEis) are known to have antifibrotic effects on the heart and kidney in both animal models and humans. N-acetyl-seryl-aspartyl-lysyl-proline is a natural inhibitor of proliferation of hematopoietic stem cells and a natural substrate of ACEi that was reported to prevent cardiac and renal fibrosis in vivo. However, it is not clear whether N-acetyl-seryl-aspartyl-lysyl-proline participates in the antifibrotic effects of ACEi. To clarify this issue, we used a model of aldosterone-salt-induced hypertension in rats treated with the ACEi captopril either alone or combined with an anti-N-acetyl-seryl-aspartyl-lysyl-proline monoclonal antibody. These hypertensive rats had the following: (1) left ventricular and renal hypertrophy, as well as increased collagen deposition in the left ventricular and the kidney; (2) glomerular matrix expansion; and (3) increased ED1-positive cells and enhanced phosphorylated-p42/44 mitogen-activated protein kinase in the left ventricle and kidney. The ACEi alone significantly lowered systolic blood pressure (Pϭ0.008) with no effect on organ hypertrophy; it significantly lowered left ventricular collagen content, and this effect was blocked by the monoclonal antibody as confirmed by the histological data. As expected, the ACEi significantly decreased renal collagen deposition and glomerular matrix expansion, and these effects were attenuated by the monoclonal antibody. Likewise, the ACEi significantly decreased ED1-positive cells and inhibited p42/44 mitogen-activated protein kinase phosphorylation in the left ventricle and kidney, and these effects were blocked by the monoclonal antibody. We concluded that in aldosterone-salt-induced hypertension, the antifibrotic effect of ACEi on the heart and kidney, is partially mediated by N-acetyl-seryl-aspartyl-lysyl-proline, resulting in decreased inflammatory cell infiltration and p42/44 mitogen-activated protein kinase activation. Key Words: aldosterone-salt Ⅲ hypertension Ⅲ angiotensin-converting enzyme inhibitor Ⅲ Ac-SDKP Ⅲ collagen Ⅲ mitogen-activated protein kinase Ⅲ macrophage/monocyte infiltration A ngiotensin (Ang)-converting enzyme (ACE) inhibitors (ACEis) are important agents for treatment of hypertension, heart failure, and other cardiovascular and renal diseases. In vivo studies showed that ACEi significantly attenuated cardiac fibrosis in rats with heart failure induced by myocardial infarction, 1 spontaneously hypertensive rats, 2 and rats with aldosterone (ALDO)-salt hypertension 3 and also prevented both cardiac and renal fibrosis in mice given deoxycorticosterone acetate-salt. 4 N-acetyl-seryl-aspartyllysyl-proline (Ac-SDKP), a natural inhibitor of hematopoietic stem cell proliferation and a natural substrate of ACEi, 5,6 was reported to inhibit rat cardiac fibroblast proliferation and collagen synthesis 7,8 and mesangial cell proliferation. 9 It also prevented left ventricular (LV) and renal fibrosis in hypertensive rats, 10,11 as well as renal insufficiency and fibrosis in diabe...
Galectin-3 (Gal-3), a member of the β-galactoside lectin family, has an important role in immune regulation. In hypertensive rats and heart failure patients, Gal-3 is considered a marker for an unfavorable prognosis. Nevertheless, the role and mechanism of Gal-3 action in hypertension-induced target organ damage are unknown. We hypothesized that, in angiotensin II (ANG II)-induced hypertension, genetic deletion of Gal-3 prevents left ventricular (LV) adverse remodeling and LV dysfunction by reducing the innate immune responses and myocardial fibrosis. To induce hypertension, male C57BL/6J and Gal-3 knockout (KO) mice were infused with ANG II (3 μg·min·kg sc) for 8 wk. We assessed: 1) systolic blood pressure by plethysmography, 2) LV function and remodeling by echocardiography, 3) myocardial fibrosis by histology, 4) cardiac CD68 macrophage infiltration by histology, 5) ICAM-1 and VCAM-1 expression by Western blotting, 6) plasma cytokines, including interleukin-6 (IL-6), by enzyme-linked immunosorbent assay, and 7) regulatory T (T) cells by flow cytometry as detected by their combined expression of CD4, CD25, and FOXP3. Systolic blood pressure and cardiac hypertrophy increased similarly in both mouse strains when infused with ANG II. However, hypertensive C57BL/6J mice suffered impaired ejection and shortening fractions. In these mice, the extent of myocardial fibrosis and macrophage infiltration was greater in histological sections, and cardiac ICAM-1, as well as plasma IL-6, expression was higher as assessed by Western blotting. However, all these parameters were blunted in Gal-3 KO mice. Hypertensive Gal-3 KO mice also had a higher number of splenic T lymphocytes. In conclusion, in ANG II-induced hypertension, genetic deletion of Gal-3 prevented LV dysfunction without affecting blood pressure or LV hypertrophy. This study indicates that the ANG II effects are, in part, mediated or triggered by Gal-3 together with the related intercellular signaling (ICAM-1 and IL-6), leading to cardiac inflammation and fibrosis.
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