Weiguo Wan

Hepatocyte growth factor regulates the TGF‑β1‑induced proliferation, differentiation and secretory function of cardiac fibroblasts

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.

Intramyocardial delivery of VEGF165 via a novel biodegradable hydrogel induces angiogenesis and improves cardiac function after rat myocardial infarction

Vascular endothelial growth factor (VEGF), an independent mitogen, has been reported to induce angiogenesis and thus attenuates the damage induced by myocardial infarction (MI). VEGF165 is the most abundant and predominant isoform of VEGF. This study investigates whether this effect could be strengthened by local intramyocardial injection of VEGF165 along with a novel biodegradable Dex-PCL-HEMA/PNIPAAm hydrogel and ascertains its possible mechanism of action. Rat models of myocardial infarction were induced by coronary artery ligation. Phosphate-buffered saline (PBS group), Dex-PCL-HEMA/PNIPAAm hydrogel (Gel group), phosphate-buffered saline containing VEGF165 (VP group), and hydrogel containing VEGF165 (VPG group) were injected into a peri-infarcted area of cardiac tissue immediately after myocardial infarction, respectively. The sham group was thoracic but without myocardial infarction. The injection of VEGF165 along with a hydrogel induced angiogenesis, reduced collagen content and MI area, inhibited cell apoptosis, increased the level of VEGF165 protein and the expression of flk-1 and flt-1, and improved cardiac function compared with the injection of either alone after MI in rats. The results suggest that injection of VEGF165 along with a hydrogel acquires more cardioprotective effects than either alone in rat with MI by sustained release of VEGF165, then may enhance the feedback between VEGF and its receptors flk-1 and flt-1.

Possible mechanism by which renal sympathetic denervation improves left ventricular remodelling after myocardial infarction.

What is the central question of this study? The enzyme system that is responsible for extracellular matrix (ECM) turnover is the matrix metalloproteinases (MMPs), which can be blocked by the tissue inhibitors of MMPs (TIMPs). Whether renal sympathetic denervation (RSD) is able to ameliorate post‐myocardial infarction left ventricular remodelling through attenuation of ECM via regulation of MMP activity and/or the MMP–TIMP complex remains unknown. What is the main finding and its importance? Renal sympathetic denervation has therapeutic effects on post‐myocardial infarction left ventricular remodelling, probably by attenuating the ECM through regulation of the MMP9–TIMP1 complex in the transforming growth factor‐β1 (a profibrotic cytokine that accelerates ECM remodelling after ischaemia) signalling pathway.

Renal sympathetic denervation improves left ventricular remodeling through regulating MMP9/TIMP1 balance and TGF-β1 following myocardial infarction.

What is the central question of this study? The enzyme system that is responsible for extracellular matrix (ECM) turnover is the matrix metalloproteinases (MMPs), which can be blocked by the tissue inhibitors of MMPs (TIMPs). Whether renal sympathetic denervation (RSD) is able to ameliorate post‐myocardial infarction left ventricular remodelling through attenuation of ECM via regulation of MMP activity and/or the MMP–TIMP complex remains unknown. What is the main finding and its importance? Renal sympathetic denervation has therapeutic effects on post‐myocardial infarction left ventricular remodelling, probably by attenuating the ECM through regulation of the MMP9–TIMP1 complex in the transforming growth factor‐β1 (a profibrotic cytokine that accelerates ECM remodelling after ischaemia) signalling pathway.

A novel, biodegradable, thermoresponsive hydrogel attenuates ventricular remodeling and improves cardiac function following myocardial infarction - a review.

Myocardial infarction (MI) and the subsequent heart failure remain among of the leading causes of morbidity and mortality in world wide. A number of studies have demonstrated that intramyocardial biomaterials injections improve cardiac function after implantation because of their angiogenic potential. Thermoresponsive hydrogels, one member of the hydrogels family, are a kind of biomaterial whose structure is similar to that of extracellular matrix. These hydrogels have been interesting for biomedical uses as they can swell in situ under physiological conditions and provide the advantage of convenient administration. The hydrogel that our team is interested in is a novel biodegradable injectable thermoresponsive hydrogel-the copolymer dextran-poly (ε-caprolactone) -2-hydroxylethyl methacrylatepoly (N-isopropylacrylaminde) (Dex-PCL-HEMA/PNIPAAm). Thus, this review will focus on requirements and challenges of injectable synthetic material, and possible mechanism of thermoresponsive hydrogel in treating MI. The main emphases are on the work done and future interesting studies in our laboratory.

Renal Sympathetic Denervation in Rats Ameliorates Cardiac Dysfunction and Fibrosis Post-Myocardial Infarction Involving MicroRNAs.

Background The role of renal sympathetic denervation (RSD) in ameliorating post-myocardial infarction (MI) left ventricular (LV) fibrosis via microRNA-dependent regulation of connective tissue growth factor (CTGF) remains unknown. Material/Methods MI and RSD were induced in Sprague–Dawley rats by ligating the left coronary artery and denervating the bilateral renal nerves, respectively. Norepinephrine, renin, angiotensin II and aldosterone in plasma, collagen, microRNA21, microRNA 101a, microRNA 133a and CTGF in heart tissue, as well as cardiac function were evaluated six weeks post-MI. Results In the RSD group, parameters of cardiac function were significantly improved as evidenced by increased LV ejection fraction (p<0.01), LV end-systolic diameter (p<0.01), end-diastolic diameter (p<0.05), LV systolic pressure (p<0.05), maximal rate of pressure rise and decline (dP/dtmax and dP/dtmin, p<0.05), and decreased LV end-diastolic pressure (p<0.05) when compared with MI rats. Further, reduced collagen deposition in peri-infarct myocardium was observed in RSD-treated rats along with higher microRNA101a and microRNA133a (p<0.05) and lower microRNA21 expression (p<0.01) than in MI rats. CTGF mRNA and protein levels were decreased in LV following RSD (p<0.01), accompanied by decreased expression of norepinephrine, renin, angiotensin II and aldosterone in plasma (p<0.05) compared with untreated MI rats. Conclusions The potential therapeutic effects of RSD on post-MI LV fibrosis may be partly mediated by inhibition of CTGF expression via upregulation of microRNA 101a and microRNA 133a and downregulation of microRNA21.

Intramyocardial delivery of bFGF with a biodegradable and thermosensitive hydrogel improves angiogenesis and cardio‑protection in infarcted myocardium

Basic fibroblast growth factor (bFGF), a known angiogenic factor, may provide a potential strategy for the treatment of myocardial infarction (MI), but it is limited by a relatively short half-life. Dex-PCL-HEMA/PNIPAAm hydrogel provides a reservoir for the controlled release of growth factors. The aim of the current study was to evaluate the effects of bFGF incorporated into a Dex-PCL-HEMA/PNIPAAm hydrogel on angiogenesis and cardiac health in a rat model of acute MI, induced by coronary artery ligation. Phosphate-buffered solution (PBS group), Dex-PCL-HEMA/PNIPAAm hydrogel (Gel group), bFGF in phosphate-buffered solution (bFGF group) or bFGF in hydrogel (Gel + bFGF group) was injected into a peri-infarcted area of cardiac tissue immediately following MI. On day 30 post-surgery, cardiac function was assessed by echocardiography, apoptosis index by terminal deoxynucleotidyl transferase dUTP nick-end labeling assessment and vascular development by immunohistochemical staining. The findings demonstrated that injection of bFGF along with hydrogel induced angiogenesis, reduced collagen content, MI area and cell apoptosis and improved cardiac function compared with the injection of either bFGF or hydrogel alone. bFGF incorporated with Dex-PCL-HEMA/PNIPAAm hydrogel injection induces angiogenesis, attenuates cardiac remodeling and improves cardiac function following MI.