Hongli Sun

Activation of peroxisome proliferator-activated receptor γ (PPARγ) through NF-κB/Brg1 and TGF-β1 pathways attenuates cardiac remodeling in pressure-overloaded rat hearts.

Background/Aims: Cardiac remodeling is a common pathophysiological change along with chronic hypertension and myocardial infarction. Recent evidence indicated that cardiac tissue expressed peroxisome proliferator-activated receptor γ (PPARγ). However, the functional role of PPARγ in cardiac remodeling remained unclear. The present study was designed to investigate the relationship between PPARγ activation and pressure overload-induced cardiac remodeling. Methods: Cardiac remodeling model was successfully established by abdominal aorta ligation. Cardiac fibrosis and cardiomyocyte hypertrophy were simulated by 100 nM angiotensin II (Ang II) in vitro. Haemodynamic parameters, the expressions of Brg1, a-MHC, ß-MHC, transforming growth factor beta 1 (TGF-ß1), collagen-I, collagen-III and NF-γB were examined. Results: Morphological and haemodynamic measurements showed that the activation of PPARγ improved the impaired cardiac function and decreased interstitial fibrosis in cardiac remodeling rats. Further results also showed that the activation of PPARγ inhibited the expressions of Brg1 and TGF-ß1 in the cardiac remodeling hearts. The activation of PPARγ also inhibited the proliferation and collagen production of cardiac fibroblasts, and down-regulated the activity of Brg1 and the expression of TGF-ß1 induced by Ang II in cultured neonatal rat cardiomyocytes and cardiac fibroblasts, respectively, through NF-γB pathway. Conclusions: These results suggested that PPARγ activation effectively inhibited cardiac remodeling processes by suppression of Brg1 and TGF-ß1 expressions through NF-γB pathway in the pressure-overloaded hearts induced by abdominal aorta ligation in rats.

Construction and analysis of cardiac hypertrophy-associated lncRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in cardiac hypertrophy

Cardiac hypertrophy (CH) could increase cardiac after-load and lead to heart failure. Recent studies have suggested that long non-coding RNA (lncRNA) played a crucial role in the process of the cardiac hypertrophy, such as Mhrt, TERMINATOR. Some studies have further found a new interacting mechanism, competitive endogenous RNA (ceRNA), of which lncRNA could interact with micro-RNAs (miRNA) and indirectly interact with mRNAs through competing interactions. However, the mechanism of ceRNA regulated by lncRNA in the CH remained unclear. In our study, we generated a global triple network containing mRNA, miRNA and lncRNA, and extracted a CH related lncRNA-mRNA network (CHLMN) through integrating the data from starbase, miRanda database and gene expression profile. Based on the ceRNA mechanism, we analyzed the characters of CHLMN and found that 3 lncRNAs (SLC26A4-AS1, RP11-344E13.3 and MAGI1-IT1) were high related to CH. We further performed cluster module analysis and random walk with restart for the CHLMN, finally 14 lncRNAs had been discovered as the potential CH related disease genes. Our results showed that lncRNA played an important role in the CH and could shed new light to the understanding underlying mechanisms of the CH.

Carvacrol inhibits proliferation and induces apoptosis in human colon cancer cells.

Colon cancer is one of the most common malignancies worldwide and has a high mortality rate. Carvacrol is a major component of oregano and thyme essential oils and shows antitumor properties. Here, we investigated the effects of carvacrol on the proliferation and apoptosis of two human colon cancer cell lines, HCT116 and LoVo, and studied the molecular mechanisms of its antitumor properties. We found that carvacrol inhibited the proliferation and migration of the two colon cancer cell lines in a concentration-dependent manner. Cell invasion was suppressed after carvacrol treatment by decreasing the expression of matrix metalloprotease-2 (MMP-2) and MMP-9. Carvacrol treatment also caused cell cycle arrest in the G2/M phase and decreased cyclin B1 expression. Finally, carvacrol induced cell apoptosis in a dose-dependent manner. At the molecular level, carvacrol downregulated the expression of Bcl-2 and induced the phosphorylation of the extracellular-regulated protein kinase and protein kinase B (p-Akt). In parallel, carvacrol upregulated the expression of Bax and c-Jun N-terminal kinase. These results indicate that carvacrol might induce apoptosis in colon cancer cells through the mitochondrial apoptotic pathway and the MAPK and PI3K/Akt signaling pathways. Together, our results suggest that carvacrol may have therapeutic potential for the prevention and treatment of colon cancer.

Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer

(1) Background: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca2+-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC); (2) Methods: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca2+]i). Flow cytometry was used to analyze cell cycle; (3) Results: TRPV3 was overexpressed in 65 of 96 (67.7%) human lung cancer cases and correlated with differentiation (p = 0.001) and TNM stage (p = 0.004). Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca2+]i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4) Conclusions: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC.

Role of carvacrol in cardioprotection against myocardial ischemia/reperfusion injury in rats through activation of MAPK/ERK and Akt/eNOS signaling pathways

ABSTRACT Carvacrol (CAR) is a compound isolated from some essential oils, many studies have demonstrated its therapeutic potential on different diseases. This study aims to evaluate the protective effect of CAR against myocardial ischemia/reperfusion (I/R) injury in rats. Male adult rats underwent ligation of the left anterior descending coronary artery (LAD) in I/R models. Rats were treated with CAR after LAD. The levels of I/R‐ induced infarct size, cardiomyocyte apoptosis and cardiac functional impairment were examined. Levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) were detected by western blotting. Cardiomyocytes induced by hypoxic reperfusion (H/R) injury were tested by Hoechst 33258. Our results revealed that CAR administration significantly protected the heart function, attenuated myocardial infarct size, increased SOD and CAT levels, reduced MDA level and especially decreased cardiomyocytes apoptosis. Western blotting showed that CAR treatment up‐regulated phosphorylated ERK (p‐ERK), while producing no impact onp38 mitogen‐activated protein kinase (p38MAPK) and c‐Jun N‐terminal kinase (JNK). The cardioprotection of CAR was reversed by the ERK inhibitor PD‐98059, demonstrating the involvement of the MAPK/ERK pathway in the anti‐apoptotic mechanisms of CAR. Besides, the results in vitro also showed the protective efficiency of CAR on cardiomyocytes H/R injury. Furthermore, pretreatment with CAR markedly increased the activation of Akt/eNOS pathway in cardiomyocytes subjected to H/R, and the protective effects of CAR were abolished in the presence of the Akt inhibitor LY294002. Therefore, the cardioprotective effects of CAR may be attributed to its antioxidant and antiapoptotic activities through activations of the MAPK/ERK and Akt/eNOS signaling pathways.

Carvacrol induces the apoptosis of pulmonary artery smooth muscle cells under hypoxia.

The abnormal apoptosis of pulmonary artery smooth muscle cells (PASMCs) is an important pathophysiological process in pulmonary vascular remodeling and pulmonary arterial hypertension (PAH). Carvacrol, an essential oil compound from oregano and thyme, has displayed antimicrobial, antitumor, and antioxidant properties. Although carvacrol has pro-apoptosis properties in tumor cells, the underlying mechanisms of carvacrol in PASMC apoptosis remain unclear. Thus, in this study, we aim to investigate the role of carvacrol in pulmonary vascular remodeling and PASMC apoptosis in hypoxia. Right Ventricular Hypertrophy Measurements and pulmonary pathomorphology data show that the ratio of the heart weight/tibia length (HW/TL), the right ventricle/left ventricle plus septum (RV/LV+S) and the medial width of the pulmonary artery increased in chronic hypoxia and were reversed by carvacrol treatment under hypoxia. Additionally, carvacrol inhibited PASMC viability, attenuated oxidative stress, induced mitochondria membrane depolarization, increased the percentage of apoptotic cells, suppressed Bcl-2 expression, decreased procaspase-3 expression, promoted caspase-3 activation, and inhibited the ERK1/2 and PI3K/Akt pathway. Taken together, these findings suggest that carvacrol attenuates the pulmonary vascular remodeling and promotes PASMC apoptosis by acting on, at least in part, the intrinsic apoptotic pathway. This process might provide us new insight into the development of hypoxic pulmonary hypertension.

The transient receptor potential vanilloid-3 regulates hypoxia-mediated pulmonary artery smooth muscle cells proliferation via PI3K/AKT signaling pathway

Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca2+‐permeant cation channels. In this study, we aim to investigate the role of TRPV3 in pulmonary vascular remodeling and PASMCs proliferation under hypoxia.

The global view of mRNA-related ceRNA cross-talks across cardiovascular diseases

Competing endogenous RNA (ceRNA) have received wide attention because they are a novel way to regulate genes through sharing microRNAs (miRNAs) that are crucial for complex processes in many diseases. However, no systematic analysis of ceRNA mechanism in cardiovascular disease (CVD) is known. To gain insights into the global properties of ceRNAs in multi-CVDs, we constructed the global view of mRNA-related ceRNA cross-talk in eight major CVDs from ~2,800 samples. We found common features that could be used to uncover similarities among different CVDs and highlighted a common core ceRNA network across CVDs. Comparative analysis of hub ceRNAs in each network revealed three types of hubs, which might play key roles in diverse biological processes. Importantly, by combining CVD-related pathway genes with ceRNA-ceRNA interactions, common modules that might exert functions in specific mechanisms were identified. In addition, our study investigated a potential mechanistic linkage between pathway cross-talk and ceRNA cross-talk. In summary, this study uncovered and systematically characterized global properties of mRNA-related ceRNA cross-talks across CVDs, which may provide a new layer for exploring biological mechanisms and shed new light on cardiology.

Activation of AMPK Attenuated Cardiac Fibrosis by Inhibiting CDK2 via p21/p27 and miR-29 Family Pathways in Rats.

Cardiac fibrosis is pathological damage associated with nearly all forms of heart disease. AMP-activated protein kinase (AMPK) is an evolutionary conserved energy-sensing enzyme. Emerging evidences indicate that AMPK plays an important role in cardiac fibrosis and cell proliferation. However, less is known about the detailed mechanism of AMPK activation on cardiac fibrosis. In this study, we found the AMPK activation improved the impaired cardiac function of cardiac fibrosis rats and decreased interstitial fibrosis. Further results indicated AMPK activation promoted p21 and p27 and inhibited CDK2 and cyclin E protein expressions both in vivo and in vitro. Moreover, AMPK activation repressed downstream transcription factor hepatocyte nuclear factor 4 alpha (HNF-4α) expression and decreased the binding of HNF-4α to TGF-β1 promoters, which eventually resulted in TGF-β1 downregulation and miR-29 family upregulation. Furthermore, miR-29, in turn, inhibited the progression of cardiac fibrosis through suppressing its target CDK2. Taken together, activation of AMPK, on the one hand, upregulated p21 and p27 expression, further inhibited CDK2 and cyclin E complex, and finally suppressed the progression of cardiac fibrosis, and, on the other hand, repressed HNF-4α expression, further downregulated the activity of TGF-β1 promoter, promoted miR-29 expression, and finally prevented the development of cardiac fibrosis.

Author Correction: The global view of mRNA-related ceRNA cross-talks across cardiovascular diseases

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.