Anti-COL1A2 (S3) Anticorps (A25556)

Previous studies showed that prostacyclin inhibited fibrosis. However, both receptors of prostacyclin, prostacyclin receptor (IP) and peroxisome proliferator-activated receptor (PPAR), are abundant in cardiac fibroblasts. Here we investigated which receptor was vital in the anti-fibrosis effect of prostacyclin. In addition, the possible mechanism involved in protective effects of prostacyclin against cardiac fibrosis was also studied. We found that beraprost, a prostacyclin analogue, inhibited angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast proliferation in a concentration-dependent and time-dependent manner. Beraprost also suppressed Ang II-induced collagen I mRNA expression and protein synthesis in cardiac fibroblasts. After IP expression was knocked down by siRNA, Ang II-induced proliferation and collagen I synthesis could no longer be rescued by beraprost. However, treating cells with different specific inhibitors of PPAR subtypes prior to beraprost and Ang II stimulation, all of the above attenuating effects of beraprost were still available. Moreover, beraprost significantly blocked transforming growth factor β (TGF β) expression as well as Smad2 phosphorylation and reduced Smad-DNA binding activity. Beraprost also increased phosphorylation of cAMP response element binding protein (CREB) at Ser133 in the nucleus. Co-immunoprecipitation analysis revealed that beraprost increased CREB but decreased Smad2 binding to CREB-binding protein (CBP) in nucleus. In conclusion, beraprost inhibits cardiac fibroblast proliferation by activating IP and suppressing TGF β-Smad signal pathway.

Th17 cells have been implicated in the pathogenesis of myocarditis. Interleukin (IL)-17A produced by Th17 cells is dispensable for viral myocarditis but essential for the progression to dilated cardiomyopathy (DCM). This study investigated whether the adenoviral transfer of the IL-17 receptor A reduces myocardial remodeling and dysfunction in viral myocarditis leading to DCM. In a mouse model of Coxsackievirus B3 (CVB3)-induced chronic myocarditis, the delivery of the adenovirus-containing IL-17 receptor A (Ad-IL17RA:Fc) reduced IL-17A production and decreased the number of Th17 cells in the spleen and heart, leading to the down-regulation of systemic TNF-α and IL-6 production. Cardiac function improved significantly in the Ad-IL17R:Fc- compared with the Ad-null-treated mice 3 months after the first CVB3 infection. Ad-IL17R:Fc reduced the left ventricle dilation and decreased the mortality in viral myocarditis, leading to DCM (56% in the Ad-IL17R:Fc versus 76% in the Ad-null group). The protective effects of Ad-IL17R-Fc on remodeling correlated with the attenuation of myocardial collagen deposition and the reduction of fibroblasts in CVB3-infected hearts, which was accompanied by the down-regulation of A distintegrin and metalloprotease with thrombospondin type 1 motifs (ADAMTS-1), Matrix metalloproteinase-2(MMP-2), and collagen subtypes I and III in the heart. Moreover, in cultured cardiac fibroblasts, IL-17A induced the expression of ADAMTS-1, MMP-2, and collagen subtypes I and III and increased the proliferation of fibroblasts. We determined that the delivery of IL-17-RA:Fc reduces cardiac remodeling, improves function, and decreases mortality in viral myocarditis leading to DCM, possibly by suppressing fibrosis. Therefore, the adenoviral transfer of the IL-17 receptor A may represent an alternative therapy for chronic viral myocarditis and its progression to DCM.

BACKGROUND:

Myocardial fibrosis is an essential hallmark of diabetic cardiomyopathy (DCM) contributing to cardiac dysfunctions. Resveratrol, an antioxidant, exerts its anti-fibrotic effect via inhibition of oxidative stress, while the underlying molecular mechanism remains largely elusive. Periostin, a fibrogenesis matricellular protein, has been shown to be associated with oxidative stress. In the present study, we investigated the role of periostin in anti-fibrotic effect of resveratrol in streptozocin (STZ)-induced diabetic heart and the underlying mechanisms.

METHODS:

Diabetic mice were induced by STZ injection. After treatment with resveratrol (5 or 25 mg/kg/day i.g) or Saline containing 0.5% carboxymethyl cellulose (CMC) for 2 months, the hearts were detected for oxidative stress and cardiac fibrosis using western blot, Masson's trichrome staining and Dihydroethidium (DHE) staining. In in vitro experiments, proliferation and differentiation of fibroblasts under different conditions were investigated through western blot, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay and immunofluorescence staining.

RESULTS:

Administration of resveratrol significantly mitigated oxidative level, interstitial fibrosis and expressions of related proteins in STZ-induced diabetic hearts. In in vitro experiments, resveratrol exhibited anti-proliferative effect on primary mouse cardiac fibroblasts via inhibiting reactive oxygen species (ROS)/extracellular regulated kinase (ERK) pathway and ameliorated myofibroblast differentiation via suppressing ROS/ERK/ transforming growth factor β (TGF-β)/periostin pathway.

CONCLUSION:

Increased ROS production, activation of ERK/TGF-β/periostin pathway and myocardial fibrosis are important events in DCM. Alleviated ROS genesis by resveratrol prevents myocardial fibrosis by regulating periostin related signaling pathway. Thus, inhibition of ROS/periostin may represent a novel approach for resveratrol to reverse fibrosis in DCM.

OBJECTIVE:

To investigate the role of PDGFR-β/PI3K/AKT signaling pathway in the myocardial fibrosis.

METHODS:

CFs were divided into following 4 groups: control group (CON), PDGF-BB group (P), PDGF-BB+IMA group (IMA), and PDGF-BB+LY294002 (LY).

RESULTS:

Immunofluorescence staining showed about 90% of cells were positive for vimentin and 10% for α-SMA. After incubation for 7 days, fluorescence microscopy revealed more than 90% of cells were positive for α-SMA, which was significantly higher than that in CON group (P < 0.01), but markedly lower than that in IMA group and LY group (P < 0.01). The mRNA and protein expression of PDGFR-β, Col I, Col III, PI3K and Akt increased dramatically at 48 h after PDGF-BB treatment when compared with CON group (P < 0.01). However, IMA and LY294002 significantly inhibited the expression of PDGFR-β and p-PI3K (P < 0.05). In addition, the mRNA expression of PDGFR-β, PI3K and Akt in IMA group and LY group was also markedly lower than those in P group (P < 0.01), and the mRNA and protein expression of Col I and Col III reduced remarkably when compared with P group (P < 0.01). Of note, the mRNA expression of PDGFR-α was comparable among 4 groups, and PDGFR-β expression after PDGF-BB treatment increased significantly when compared with PDGFR-α expression (P < 0.01).

CONCLUSION:

PDGF-BB may induce CF proliferation and their transformation into myofibroblasts, which leads to increased synthesis of collagen, resulting in myocardial fibrosis. This is closely associated with PDGFR-β, but not PDGFR-α. PDGFR-β/PI3K/Akt signaling pathway is involved in the PDGF-BB induced myocardial fibrosis.

BACKGROUND:

Pulmonary fibrosis occurs in approximately 60% of patients with acute respiratory distress syndrome and has been significantly correlated with a poor outcome. The overexpression of angiotensin (Ang) II can induce lung inflammation and fibrosis. This observation, coupled with the knowledge that Ang-(1-7) is considered to be an endogenous antagonist of Ang II, led us to hypothesize that Ang-(1-7) would prevent lung remodeling in patients with acute respiratory distress syndrome.

MATERIALS AND METHODS:

The protocol involved five groups: (1) control, (2) lipopolysaccharide (LPS), (3) losartan as a positive control group, (4) Ang-(1-7), and (5) [D-Ala7]-Ang-(1-7) (A779), an antagonist of the Ang-(1-7) receptor. Acute lung injury was induced by an intratracheal injection of LPS 5 mg/kg in C57BL/6 mice. Losartan (10 mg/kg) was administered by gavage daily, starting from 1 d before LPS stimulation. Ang-(1-7) or A779 in saline (100 ng/kg/min) was infused subcutaneously 1 h before acute lung injury induction for 3 or 7 d. The lung tissues were harvested for analysis at day 3 or 7 after injection of LPS.

RESULTS:

LPS stimulation resulted in significantly increased inflammation, edema, and lung collagen production. With Ang-(1-7) treatment, the lung fibrosis score and hydroxyproline level were significantly reduced, and the expression of transforming growth factor-β and Smad2/3 were decreased on days 3 and 7. Losartan attenuated lung fibrosis similarly to Ang-(1-7) after LPS exposure. In the A779 group, a tendency was seen to aggravate collagen deposition and lung remodeling.

CONCLUSIONS:

These findings indicate an antiremodeling role for Ang-(1-7) in acute lung injury, similar to the blocker of Ang II receptor, that might be at least partially mediated through an Ang-(1-7) receptor.

Copyright © 2013 Elsevier Inc. All rights reserved.