Apolipoprotein-AI and AIBP synergetic anti-inflammation as vascular diseases therapy: the new perspective.

Vascular diseases (VDs) including pulmonary arterial hypertension (PAH), atherosclerosis (AS) and coronary arterial diseases (CADs) contribute to the higher morbidity and mortality worldwide. Apolipoprotein A-I (Apo A-I) binding protein (AIBP) and Apo-AI negatively correlate with VDs. However, the mechanism by which AIBP and apo-AI regulate VDs still remains unexplained. Here, we provide an overview of the role of AIBP and apo-AI regulation of vascular diseases molecular mechanisms such as vascular energy homeostasis imbalance, oxidative and endoplasmic reticulum stress and inflammation in VDs. In addition, the role of AIBP and apo-AI in endothelial cells (ECs), vascular smooth muscle (VSMCs) and immune cells activation in the pathogenesis of VDs are explained. The in-depth understanding of AIBP and apo-AI function in the vascular system may lead to the discovery of VDs therapy.

High-density lipoprotein-mediated cardioprotection in heart failure.

The prevalence of heart failure (HF), including reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), has increased significantly worldwide. However, the prognosis and treatment of HF are still not good. Recent studies have demonstrated that high-density lipoprotein (HDL) plays an important role in cardiac repair during HF. The exact role and mechanism of HDL in the regulation of HF remain unexplained. Here, we discuss recent findings regarding HDL in the progression of HF, such as the regulation of excitation-contraction coupling, energy homeostasis, inflammation, neurohormone activation, and microvascular dysfunction. The effects of HDL on the regulation of cardiac-related cells, such as endothelial cells (ECs), cardiomyocytes (CMs), and on cardiac resident immune cell dysfunction in HF are also explained. An in-depth understanding of HDL function in the heart may provide new strategies for the prevention and treatment of HF.

Enhancing Matured Stem-Cardiac Cell Generation and Transplantation: A Novel Strategy for Heart Failure Therapy.

Heart failure (HF) remains one of the major causes of morbidity and mortality worldwide. Recent studies have shown that stem cells (SCs) including bone marrow mesenchymal stem (BMSC), embryonic bodies (EB), embryonic stem (ESC), human induced pluripotent stem (hiPSC)-derived cardiac cells generation, and transplantation treated myocardial infarction (MI) in vivo and in human. However, the immature phenotypes compromise their clinical application requiring immediate intervention to improve stem-derived cardiac cell (S-CCs) maturation. Recently, an unbiased multi-omic analysis involving genomics, transcriptomics, epigenomics, proteomics, and metabolomics identified specific strategies for the generation of matured S-CCs that may enhance patients' recovery processes upon transplantation. However, these strategies still remain undisclosed. Here, we summarize the recently discovered strategies for the matured S-CC generation. In addition, cardiac patch formation and transplantation that accelerated HF recuperation in clinical trials are discussed. A better understanding of this work may lead to efficient generation of matured S-CCs for regenerative medicine. Graphical abstract.

Bilirubin in metabolic syndrome and associated inflammatory diseases: New perspectives.

Diabetes mellitus is one of the major global health issues, which is closely related to metabolic dysfunction and the chronic inflammatory diseases. Multiple studies have demonstrated that serum bilirubin is negatively correlated with metabolic syndrome and associated inflammatory diseases, including atherosclerosis, hypertension, etc. However, the roles of bilirubin in metabolic syndrome and associated inflammatory diseases still remain unclear. Here, we explain the role of bilirubin in metabolic syndrome and chronic inflammatory diseases and its therapeutic potential. Understanding the role of bilirubin activities in diabetes may serve as a therapeutic target for the treatment of chronic inflammatory diseases in diabetic patients.

HiPS-Cardiac Trilineage Cell Generation and Transplantation: a Novel Therapy for Myocardial Infarction.

Despite primary percutaneous coronary intervention (PPCI) and the availability of optimal medications, including dual antiplatelet therapy (DAPT), most patients still experience major adverse cardiovascular events (MACEs) due to frequent recurrence of thrombotic complications and myocardial infarction (MI). MI occurs secondary to a massive loss of endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and cardiomyocytes (CMs). The adult cardiovascular system gradually loses the ability to spontaneously and regularly regenerate ECs, VSMCs, and CMs. However, human cells can be induced by cytokines and growth factors to regenerate human-induced pluripotent stem cells (hiPSCs), which progress to produce cardiac trilineage cells (CTCs) such as ECs, VSMCs, and CMs, replacing lost cells and inducing myocardial repair. Nevertheless, the processes and pathways involved in hiPSC-CTC generation and their potential therapeutic effects remain unknown. Herein, we provide evidence of in vitro CTC generation, the pathways involved, in vivo transplantation, and its therapeutic effect, which may provide novel targets in regenerative medicine for the treatment of cardiovascular diseases (CVDs).

Perivascular adipose tissue dysfunction aggravates adventitial remodeling in obese mini pigs via NLRP3 inflammasome/IL-1 signaling pathway.

Perivascular adipose tissue (PVAT), a special type of adipose tissue, closely surrounds vascular adventitia and produces numerous bioactive substances to maintain vascular homeostasis. PVAT dysfunction has a crucial role in regulating vascular remodeling, but the exact mechanisms remain unclear. In this study, we investigated whether and how obesity-induced PVAT dysfunction affected adventitia remodeling in early vascular injury stages. Mini pigs were fed a high sugar and fat diet for 6 months to induce metabolic syndrome and obesity. In the mini pigs, left carotid vascular injury was then generated using balloon dilation. Compared with normal mini pigs, obese mini pigs displayed significantly enhanced vascular injury-induced adventitial responses, evidenced by adventitia fibroblast (AF) proliferation and differentiation, and adventitia fibrosis, as well as exacerbated PVAT dysfunction characterized by increased accumulation of resident macrophages, particularly the M1 pro-inflammatory phenotype, increased expression of leptin and decreased expression of adiponectin, and production of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. Primary AFs cultured in PVAT-conditioned medium from obese mini pigs also showed significantly increased proliferation and differentiation. We further revealed that activated nod-like receptor protein 3 (NLRP3) inflammasome and its downstream products, i.e., IL-1 family members such as IL-1ß and IL-18 were upregulated in the PVAT of obese mini pigs; PVAT dysfunction was also demonstrated in preadipocytes treated with palmitic acid. Finally, we showed that pretreatment with IL-1 receptor (IL-1R) antagonist or IL-1R knockdown blocked AF proliferation and differentiation in AFs cultured in PVAT-conditioned medium. These results demonstrate that obesity-induced PVAT dysfunction aggravates adventitial remodeling after early vascular injury with elevated AF proliferation and differentiation via activating the NLRP3/IL-1 signaling pathway.

Ghrelin attenuates myocardial fibrosis after acute myocardial infarction via inhibiting endothelial-to mesenchymal transition in rat model.

Ghrelin, a peptide hormone produced in the gastrointestinal tract, has recently been found to be associated with the onset of myocardial fibrosis (MF). The exact mechanism, however, remains elusive. This study sought to identify the function and mechanism of ghrelin on MF after acute myocardial infarction (AMI). AMI was established in Spraque-Dawley rats by ligation of the left anterior descending (LAD). Ghrelin or saline was intraperitoneally injected two times per day for 8 weeks after ligation. The weight of heart (mg) and the weight ratio of heart to body (mg/g) as well as the fibrotic area were increased, while serum level of ghrelin was decreased after AMI. Ghrelin significantly ameliorated MF and decreased deposition of collagens in perivascular fibrosis area. In addition, ghrelin inhibited Endothelial-to-mesenchymal transition (EndMT), a crucial process for MF, in perivascular fibrosis area and TGF-ß1-induced human coronary artery endothelial cells (HCAECs). Mechanistically, ghrelin persistently decreased the phosphorylation of Smad2/3 and enhanced the expression of Smad7 and p-AMPK in vivo and in vitro. After the abolition of Smad7, GHSR-1a and AMPK pathway, the effect of ghrelin on EndMT was significantly inhibited. In conclusion, these results presented a novel finding that ghrelin attenuated MF after AMI via regulation EndMT in a GHSR-1a/AMPK/Smad7- dependent manner.

Micro-environment and intracellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases.

The accumulation and pro-inflammatory polarization of immune cells, mainly macrophages, in adipose tissue (AT) are considered crucial factors for obesity-induced chronic inflammatory diseases. In this review, we highlighted the role of adipose tissue macrophage (ATM) polarization on AT function in the obese state and the effect of the micro-environment and intracellular metabolism on the dynamic switch of ATMs into their pro-inflammatory or anti-inflammatory phenotypes, which may have distinct influences on obesity-related chronic inflammatory diseases. Obesity-associated metabolic dysfunctions, including those of glucose, fatty acid, cholesterol, and other nutrient substrates such as vitamin D and iron in AT, promote the pro-inflammatory polarization of ATMs and AT inflammation via regulating the interaction between ATMs and adipocytes and intracellular metabolic pathways, including glycolysis, fatty acid oxidation, and reverse cholesterol transportation. Focusing on the regulation of ATM metabolism will provide a novel target for the treatment of obesity-related chronic inflammatory diseases, including insulin resistance, cardiovascular diseases, and cancers.

Apolipoprotein A1 Inhibits the TGF-ß1-Induced Endothelial-to-Mesenchymal Transition of Human Coronary Artery Endothelial Cells.

OBJECTIVE: Transforming growth factor ß1 (TGF-ß1) is the major cytokine for stimulating endothelial cells (ECs) to transdifferentiate to mesenchymal cells (MCs) in the process known as endothelial-to-mesenchymal transition (EndMT). Recently, TGF-ß1-induced EndMT has been implicated in the pathogenesis of atherosclerosis (AS). It has been identified that apolipoprotein A1 (ApoA-I) obstructs TGF-ß1-induced endothelial dysfunction, providing a protective effect for ECs and also anti-AS activity. However, the exact role of ApoA-I in TGF-ß1-induced EndMT is not clear. In this study, we aimed to investigate whether ApoA-I can modulate TGF-ß1-induced EndMT in human coronary artery ECs (HCAECs). METHODS AND RESULTS: The HCAECs were treated with TGF-ß1 with or without ApoA-I. Morphological changes in HCAECs and the expression of EndMT-related markers were evaluated. HCAECs treated with TGF-ß1 were found to transform to MC morphology, with inconspicuous expression of EC markers such as vascular endothelial cadherin and CD31, and conspicuous expression of fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin. The treatment of HCAECs with ApoA-I inhibited the TGF-ß1-induced EndMT, and elevated expression of EC markers was observed but reduced expression of MC markers. Moreover, ApoA-I impeded the expression level of Slug and Snail, crucial transcriptional factors of EndMT, and it inhibited the TGF-ß1-induced phosphorylation of Smad2 and Smad3 which affected the EC morphology. In addition, the knockdown of ABCA1 by RNA interference eliminated the inhibition effect of ApoA-I on TGF-ß1-induced EndMT. CONCLUSIONS: Our findings revealed a novel mechanism for the ApoA-I protective effect on endothelium function via the inhibition of TGF-ß1-induced EndMT. This might provide new insights for developing strategies for modulating AS and vascular remodeling.

Endothelial-to-mesenchymal transition: A novel therapeutic target for cardiovascular diseases.

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype. Similar to epithelial-to-mesenchymal transition (EMT), EndMT can be induced by multiple stimulants such as cytokines and metabolic factors that play crucial roles in the development of the cardiovascular system. Recent studies have demonstrated that EndMT may play a significant role in the pathogenesis of cardiovascular diseases (CVDs), and may represent a novel therapeutic target for cardiovascular remodeling and fibrotic disorders. The exact molecular mechanisms involved in cardiovascular pathogenesis that occur as a result of EndMT, however, are not fully explained. In this review, we reveal the multiple intercellular mechanisms of EndMT including stimulants, signaling pathways, and seek to explore the relationship between this biological process, cardiovascular system development, and CVDs that may lead to new therapeutic strategies for the treatment of CVDs.