Cardiac fibroblast (CF) proliferation and transformation into myofibroblasts play important roles in cardiac fibrosis during pathological myocardial remodeling. In this study, we demonstrate that hepatocyte growth factor (HGF), an antifibrotic factor in the process of pulmonary, renal and liver fibrosis, is a negative regulator of cardiac fibroblast transformation in response to transforming growth factor-β1 (TGF-β1). HGF expression levels were significantly reduced in the CFs following treatment with 5 ng/ml TGF-β1 for 48 h. The overexpression of HGF suppressed the proliferation, transformation and the secretory function of the CFs following treatment with TGF-β1, as indicated by the attenuated expression levels of α-smooth muscle actin (α-SMA) and collagen I and III, whereas the knockdown of HGF had the opposite effect. Mechanistically, we identified that the phosphorylation of c-Met, Akt and total protein of TGIF was significantly inhibited by the knockdown of HGF, but was significantly enhanced by HGF overexpression. Collectively, these results indicate that HGF activates the c-Met-Akt-TGIF signaling pathway, inhibiting CF proliferation and transformation in response to TGF-β1 stimulation.

Bioabsorbable drug-eluting stents (BDES) offer multiple advantages over a permanent bare metal stent (BMS) for coronary artery disease (CAD). However, current BDES remains two major issues: inferior radial strength and biocompatibility. PowerStent Absorb BDES, fabricated by co-formulating amorphous calcium phosphate (ACP) nanoparticles with poly-L-lactic acid (PLLA/ACP, 98/2, w/w) and 2% Paclitaxel (PAX, w/w) was designed to address these issues. Two cohorts of 6 miniature pigs were each implanted with PLLA/PAX (control, 2% PAX, w/w) or PowerStent Absorb BDES. After 1 month in-vivo study, histological analyses showed significantly reduced restenosis in the PowerStent Absorb BDES cohort relative to the control cohort (44.49 +/- 410.49% vs. 64.47 +/- 16.2%, p < 0.05). Stent recoil (21.57 +/- 5.36% vs. 33.81 +/- 11.49, P < 0.05) and inflammation (3.01 +/- 0.62 vs. 4.07 +/- 0.86, P < 0.01) were also obviously decreased. From in-vitro studies, PLLA/ACP/PAX stent tube maintained significantly greater radial strength than control group during 6 months in-vitro degradation (PLLA/ACP/PAX vs. PLLA/PAX: before hydrolysis: 82.4 +/- 1.9 N vs.74.8 +/- 3.8 N; 6 weeks: 73.9 +/- 1.8 N vs. 68.0 +/- 5.3 N; 3 months: 73.5 +/- 3.4 N vs.67.2 +/- 3.8 N; 6 months: 56.3 +/- 8.1 N vs. 57.5 +/- 4.9 N). Moreover, ACP facilitated the hydrolytic degradation of PLLA compared with control one (62.6% vs. 49.8%), meanwhile, it also increased the crystallinity of PLLA (58.4% vs. 50.7%) at 6 months. From SEM observations, ACP created nanometer pores that enlarge gradually to a micrometer scale as degradation proceeds. The changes of the porosity may result in greatly promoting re-endothelialization.

To study the effect of novel bioresorbable scaffold composed of poly-L-lactic acid (PLLA) and amorphous calcium phosphate (ACP) nanoparticles on inflammation and calcification of surrounding tissues after implantation. Ninety six PLLA/ACP scaffolds and 96 PLLA scaffolds were randomly implanted in the back muscle tissue of 48 SD rats. At the 1st, 2nd, 4th, and 12th weeks after implantation, the calcium, phosphorus, and alkaline phosphatase levels in the blood serum and the contents of calcium and alkaline phosphatase in the tissue surrounding the scaffolds were measured. Hematoxylin-eosin staining was performed to count the inflammatory cells. Von kossa staining was performed to observe calcification of the surrounding tissue around the scaffold. NF-κB staining was performed by immunohistochemistry to calculate the positive expression index of inflammatory cells. Western blot was used to detect the expression of IL-6 and BMP-2 in the tissues surrounding the scaffolds. At the 1st, 2nd, 4th, and 12th weeks after scaffold implantation, there were no significant difference in the serum concentration of calcium, phosphorus, alkaline phosphatase and in the tissue homogenate concentration of alkaline phosphatase between the two groups (P > 0.05). The level of calcium in tissue homogenates was lower in the PLLA/ACP group than in the PLLA group at 12-week (P < 0.05). The hematoxylin-eosin staining results showed that the inflammatory cell count in the PLLA/ACP group was lower than the PLLA group at 4-week and 12-week (P < 0.05). The results of NF-kB positive expression index showed that the PLLA group was significantly more than the PLLA/ACP group at 4-week and 12-week (P < 0.01). Western blot results showed that IL-6 expression levels in the PLLA/ACP group scaffolds were significantly lower than those in the control group at the 2-week, 4-week and 12-week (P < 0.05). The expression of BMP-2 in the PLLA group was significantly lower than that in the control group at 4-week and 12-week (P < 0.05). The PLLA/ACP composite material has good histocompatibility. The integration of nanoscale ACPs reduces the inflammatory response induced by acidic metabolites of PLLA material and may inhibit tissue calcification by reducing the amount of calcification factors in the body.

Our previous studies have confirmed the superior biocompatibility of the poly-L-lactic acid/amorphous calcium phosphate (PLLA/ACP) scaffolds (PowerScaffold) compared to PLLA scaffolds and their similar 6-month radial strength compared with TAXUS stents. In order to conduct further dynamic observations on the performance of the PowerScaffold after 12-month implantation compared with the TAXUS stents. Twenty PowerScaffold and 20 TAXUS were implanted in porcine coronary arteries. At 12-month follow-up, Quantitative Coronary Angiography showed that the stent reference vessel diameter (3.19 ± 0.25 mm vs. 2.75 ± 0.22 mm, p < 0.05), the mean lumen diameter (3.07 ± 0.22 mm vs. 2.70 ± 0.17 mm, p < 0.05) and the late lumen gain (0.45 ± 0.07 mm vs. 0.06 ± 0.06 mm, p < 0.01) were all significantly greater with the PowerScaffold than the TAXUS. As well, Intravascular Ultrasound showed the stent reference vessel area (7.74 ± 0.48 mm2 vs. 6.96 ± 0.51 mm2, p < 0.05), the mean stent area (7.49 ± 0.46 mm2 vs. 6.53 ± 0.47 mm2, p < 0.05) and the mean lumen area (7.22 ± 0.50 mm2 vs. 6.00 ± 0.48 mm2, p < 0.01) were all significantly greater with the PowerScaffold than the TAXUS. The luminal patency rate of the PowerScaffold significantly increased from 72.45 ± 6.84% at 1 month to 93.54 ± 8.15% at 12 months (p < 0.01) while the TAXUS stents were associated with a non-significant decreasing trend (89.44 ± 8.44% vs. 86.53 ± 8.22%). Pathology indicated the average thickness of the struts degraded by 14.25 ± 3.04 μm at 1 month, 23.39 ± 2.45 μm at 6 months and 35.54 ± 2.20 μm at 12 months. Immunohistochemical examination showed that the expression of inflammatory factors NF-κB gradually decreased from 1-month to 12-month (36.79 ± 4.78 vs. 5.79 ± 2.85, P < 0.01). As the late lumen gain of arteries implanted with the PowerScaffold increases over time with the growth of vessels, it effectively reverse the late vascular negative remodeling observed with the TAXUS stents, providing a better option for lumen restoration treatment in clinical practice.

Using poly-L-lactic acid for implantable biodegradable scaffold has potential biocompatibility issue due to its acidic degradation byproducts. We have previously reported that the addition of amorphous calcium phosphate improved poly-L-lactic acid coating biocompatibility. In the present study, poly-L-lactic acid and poly-L-lactic acid/amorphous calcium phosphate scaffolds were implanted in pig coronary arteries for 28 days. At the follow-up angiographic evaluation, no case of stent thrombosis was observed, and the arteries that were stented with the copolymer scaffold had significantly less inflammation and nuclear factor-κB expression and a greater degree of reendothelialization. The serum levels of vascular endothelial growth factor and nitric oxide, as well the expression of endothelial nitric oxide synthase and platelet-endothelial cell adhesion molecule-1, were also significantly higher. In conclusion, the addition of amorphous calcium phosphate to biodegradable poly-L-lactic acid scaffold minimizes the inflammatory response, promotes the growth of endothelial cells, and accelerates the reendothelialization of the stented coronary arteries.

At six-month post-implantation, the PowerStent Absorb stents maintained their structural strength and functional performance. The development of restenosis was controlled, no stent thrombosis was observed and the stents were fully re-endothelialized. These results suggest the PowerStent Absorb stent is safe and effective for up to 6 months when implanted in porcine coronary arteries.

No abstract

No abstract