Interplay Between TGF-ß Signaling and MicroRNA in Diabetic Cardiomyopathy.

In diabetic patients, concomitant cardiovascular disease is the main factor contributing to their morbidity and mortality. Diabetic cardiomyopathy (DCM) is a form of cardiovascular disease associated with diabetes that can result in heart failure. Transforming growth factor-ß (TGF-ß) isoforms play a crucial role in heart remodeling and repair and are elevated and activated in myocardial disorders. Alterations in certain microRNAs (miRNA) are closely related to diabetic cardiomyopathy. One or more miRNA molecules target the majority of TGF-ß pathway components, and TGF-ß directly or via SMADs controls miRNA synthesis. Based on these interactions, this review discusses potential cross-talk between TGF-ß signaling and miRNA in DCM in order to investigate the creation of potential therapeutic targets.

ZNF667 Suppressed LPS-induced Macrophages Inflammation through mTOR-dependent Aerobic Glycolysis Regulation.

BACKGROUND: Macrophages participate in all stages of the inflammatory response, and the excessive release of inflammatory mediators and other cytokines synthesized and secreted by macrophages is fundamentally linked to an uncontrolled inflammatory response. The zinc finger 667 (ZNF667) protein, a novel DNAbinding protein, has been shown to play a vital role in oxidative stress. However, none of the target genes in macrophages or the potential roles of ZNF667 have been elucidated to date. > Objectives: The present study was designed to investigate the effects of ZNF667 on LPS-induced inflammation in macrophages. > Methods: The RAW264.7 macrophage cell line was selected as a model system. Inflammatory response-related gene expression levels and phosphorylation levels of PI3K, AKT, and mTOR were detected in LPS-treated macrophages via RT-PCR and western blotting, respectively. > Results: We found that LPS resulted in the up-regulation of ZNF667 in macrophages and a peak response in ZNF667 protein expression levels when used at a concentration of 100 ng/mL. ZNF667 overexpression significantly inhibited the LPS-induced up-regulation of iNOS, and IL-1ß mRNA and protein expression levels, together with the secretion of IL-1ß, IL-6, and TNF-α. ZNF667 overexpression also inhibited PI3K, AKT, and mTOR hyperphosphorylation and had no effect on the phosphorylation of NF-κB p65, ERK1/2, MAPK p38, and the transcriptional activity of NF-κB in macrophages. The up-regulation of ZNF667 inhibited the levels of expression of HK2 and PFKFB3, glucose consumption, and lactate production in LPS-stimulated macrophages. The up-regulation of mRNA levels of LPS-induced glycolytic genes HK2 and PFKFB3 and the increased mRNA expression of pro-inflammatory cytokines (IL-1ß and iNOS) were abolished by hexokinase inhibitor 2-DG in ZNF667-deficient macrophages. Meanwhile, glucose consumption and lactate production were abrogated in macrophages when cells were treated with the specific mTOR inhibitor RPM. > Conclusion: Our results demonstrate that ZNF667 suppressed LPS-stimulated RAW264.7 macrophage inflammation by regulating mTOR-dependent aerobic glycolysis.>.

MicroRNA-223-3p promotes pyroptosis of cardiomyocyte and release of inflammasome factors via downregulating the expression level of SPI1 (PU.1).

Diabetic cardiomyopathy (DCM) is a common heart disease in patients with diabetes mellitus (DM), and is sometimes its main cause of death. Among all the causes of DCM, myocardial cell death is considered to be the most basic pathological change. Furthermore, studies have shown that pyroptosis, the pro-inflammatory programmed cell death, contributes to the progress of DCM. MicroRNAs (miRNAs) also have been proved to take part in the formation of DCM. However, it is not clear whether and how miRNAs regulate myocardial cell pyroptosis in DCM development. In our study, the results showed that the expression of miR-223-3p was significantly increased in cardiomyocytes induced by high glucose, whereas the down-regulation of miR-223-3p weakened it. To understand the signal transduction mechanism of miR-223-3p leading to pyroptosis, we found inhibition of miR-223-3p expression down-regulated caspase-1, pro-inflammatory cytokines IL-1ß and other pyroptosis-associated poteins. Moreover, miR-223-3p repressed SPI1 expression. Furthermore, we silenced SPI1 with siRNA to mimic the effect of miR-223-3p, up-regulating the expression of caspase-1 and resulting to pyroptosis. The above findings inspired us to propose a new signaling pathway to regulate scoria of cardiomyocytes under hyperglycemia: miR-223-3p↑→ SPI1↓→ caspase-1↑ → IL-1ß and other pyroptosis-associated poteins↑→ pyroptosis↑. In summary, miR-223-3p could be a potential therapeutic target for DCM.

Farnesoid X Receptor Deficiency Induces Hepatic Lipid and Glucose Metabolism Disorder via Regulation of Pyruvate Dehydrogenase Kinase 4.

Farnesoid X receptors (FXR) are bile acid receptors that play roles in lipid, glucose, and energy homeostasis. Synthetic FXR-specific agonists have been developed for treating nonalcoholic fatty liver disease (NAFLD) patients. However, the detailed mechanism remains unclear. To investigate the effects of FXR on NAFLD and the possible mechanism, FXR-null mice were fed either a normal or a high-fat diet. The FXR-null mice developed hepatomegaly, steatosis, accumulation of lipid droplets in liver cells, glucose metabolism disorder, and elevated serum lipid levels. Transcriptomic results showed increased expression of key lipid synthesis and glucose metabolism-related proteins. We focused on pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme involved in the regulation of glucose and fatty acid (FA) metabolism and homeostasis. Subsequently, we confirmed an increase in PDK4 expression in FXR knockout cells. Moreover, inhibition of PDK4 expression alleviated lipid accumulation in hepatocytes caused by FXR deficiency in vivo and in vitro. Our results identify FXR as a nuclear transcription factor that regulates glucose and lipid metabolism balance through PDK4, providing further insights into the mechanism of FXR agonists in the treatment of metabolic diseases.

Cardiovascular protective effects of GLP-1: a focus on the MAPK signaling pathway.

Cardiovascular and related metabolic diseases are significant global health challenges. Glucagon-like peptide 1 (GLP-1) is a brain-gut peptide secreted by the ileal endocrine system and is now an established drug target in type 2 diabetes (T2DM). GLP-1 targeting agents have been shown not only to treat T2DM, but also to exert cardiovascular protective effects by regulating multiple signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, a common signal transduction pathway for transmitting extracellular signals to downstream effector molecules, is involved in regulating diverse cellular physiological processes, including cell proliferation, differentiation, stress, inflammation, functional synchronization, transformation, and apoptosis. The purpose of this review is to highlight the relationship between GLP-1 and cardiovascular disease (CVD) and discuss how GLP-1 exerts cardiovascular protective effects through the MAPK signaling pathway. This review also discusses the future challenges in fully characterizing and evaluating the CVD protective effects of GLP-1 receptor agonists (GLP-1RA) at the cellular and molecular levels. A better understanding of the MAPK signaling pathway that is dysregulated in CVD may aid in the design and development of promising GLP-1RA.

Hydrogen Sulfide Ameliorates Angiotensin II-Induced Atrial Fibrosis Progression to Atrial Fibrillation Through Inhibition of the Warburg Effect and Endoplasmic Reticulum Stress.

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-ß-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.

Targeting the microRNAs in exosome: A potential therapeutic strategy for alleviation of diabetes-related cardiovascular complication.

Diabetes-related cardiovascular disease (CVD) is a global health issue that causes thousands of people's death around the world annually. Diabetes-related CVD is still prevailing despite the progression being made in its diagnosis and treatment. Therefore it is urgent to find therapeutic strategies.to prevent it. MicroRNA (miRNA) is a single-stranded non-coding RNA involved in the process of post-transcriptional control of gene expression in eukaryotes. A large number of literatures reveal that miRNAs are implicated in diabetes-related CVD. The increase of miRNAs in exosomes may promote the occurrence and development of diabetes-related cardiovascular complication. However, some other studies identify that miRNAs in exosomes are supposed to be involved in cardiac regeneration and confer cardiac protection effect. Therefore, targeting the miRNA in exosome is regarded as a potent therapeutic measure to alleviate diabetes-related CVD. In this article, we review current knowledge about the role of exosomal miRNAs in diabetes-related cardiovascular complication, such as coronary heart disease, Peripheral artery disease, stroke, diabetic cardiomyopathy, diabetic nephropathy and diabetic retinopathy. Exosomal miRNAs are considered to be central regulators of diabetes-Related CVD and provide a therapeutic tool for diagnosis and treatment of diabetes-related cardiovascular complication.

Oxidative stress in vascular calcification.

Vascular calcification (VC), which is closely associated with significant mortality in cardiovascular disease, chronic kidney disease (CKD), and/or diabetes mellitus, is characterized by abnormal deposits of hydroxyapatite minerals in the arterial wall. The impact of oxidative stress (OS) on the onset and progression of VC has not been well described. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, myeloperoxidase (MPO), nitric oxide synthases (NOSs), superoxide dismutase (SOD) and paraoxonases (PONs) are relevant factors that influence the production of reactive oxygen species (ROS). Furthermore, excess ROS-induced OS has emerged as a critical mediator promoting VC through several mechanisms, including phosphate balance, differentiation of vascular smooth muscle cells (VSMCs), inflammation, DNA damage, and extracellular matrix remodeling. Because OS is a significant regulator of VC, antioxidants may be considered as novel treatment options.

PIWI-interacting RNAs and PIWI proteins in diabetes and cardiovascular disease: Molecular pathogenesis and role as biomarkers.

Cardiovascular disease (CVD) is still one of the most significant diseases and is a considerable threat to human health globally. PIWI-interacting RNAs (piRNAs) are novel small noncoding RNAs (ncRNAs) traditionally considered to be specifically expressed in the germline of many animal species and involved in the maintenance of germline stem cells and spermatogenesis. Although little is known about the origin and action of piRNAs and PIWI proteins in somatic cells, these molecules are emerging as readily available biomarkers for the diagnosis and treatment of cardiac injury and multiform CVD. Accumulating evidence reveals that piRNAs and PIWI proteins are associated with some molecular and cellular pathways in CVD. Here, we summarize recent evidence and evaluate the molecular mechanism of the involvement of piRNAs and PIWI proteins in CVD.

CircRNAs in diabetic cardiomyopathy.

Diabetic cardiomyopathy is an important irreversible chronic cardiovascular complication in diabetic patients. This condition is described as early diastolic dysfunction, myocardial fibrosis, cardiac hypertrophy, systolic dysfunction and other complex pathophysiological events, which ultimately lead to heart failure. Despite these characteristics, the underlying mechanisms resulting in diabetic cardiomyopathy are still unknown. With the developments in molecular biotechnology, increasing evidence shows that circRNAs play critical roles in the pathogenesis of diabetic cardiomyopathy. The purpose of this review is to summarize recent studies on the role of circRNAs in the pathophysiological process to provide novel prevention and treatment strategies for diabetic cardiomyopathy, oxidative stress, inflammation, endothelial dysfunction, myocardial fibrosis and cell death in diabetic cardiomyopathy.

Hydrogen sulfide improves ox­LDL­induced expression levels of Lp­PLA2 in THP­1 monocytes via the p38MAPK pathway.

Hydrogen sulfide (H2S) exerts an anti­atherosclerotic effect and decreases foam cell formation. Lipoprotein­associated phospholipase A2 (Lp­PLA2) is a key factor involved in foam cell formation. However, the association between H2S and Lp­PLA2 expression levels with respect to foam cell formation has not yet been elucidated. The present study investigated whether H2S can affect foam cell formation and potential signalling pathways via regulation of the expression and activity of Lp­PLA2. Using human monocytic THP­1 cells as a model system, it was observed that oxidized low­density lipoprotein (ox­LDL) not only upregulates the expression level and activity of Lp­PLA2, it also downregulates the expression level and activity of Cystathionine γ lyase. Exogenous supplementation of H2S decreased the expression and activity of Lp­PLA2 induced by ox­LDL. Moreover, ox­LDL induced the expression level and activity of Lp­PLA2 via activation of the p38MAPK signalling pathway. H2S blocked the expression levels and activity of Lp­PLA2 induced by ox­LDL via inhibition of the p38MAPK signalling pathway. Furthermore, H2S inhibited Lp­PLA2 activity by blocking the p38MAPK signaling pathway and significantly decreased lipid accumulation in ox­LDL­induced macrophages, as detected by Oil Red O staining. The results of the present study indicated that H2S inhibited ox­LDL­induced Lp­PLA2 expression levels and activity by blocking the p38MAPK signalling pathway, thereby improving foam cell formation. These findings may provide novel insights into the role of H2S intervention in the progression of atherosclerosis.

Adipokines in vascular calcification.

Adipose tissue (AT), a critical endocrine gland, is capable of producing and secreting abundant adipokines. Adipokines act on distant or adjacent organ tissues via paracrine, autocrine, and endocrine mechanism, which play attractive roles in the regulation of glycolipid metabolism and inflammatory response. Increasing evidence shows that adipokines can connect obesity with cardiovascular diseases by serving as promoters or inhibitors in vascular calcification. The chronic hypoxia in AT, caused by the adipocyte hypertrophy, is able to trigger imbalanced adipokine generation, which leads to apoptosis, osteogenic differentiation of vascular smooth muscle cells (VSMCs), vascular inflammation, and abnormal deposition of calcium and phosphorus in the vessel wall. The objectives of this review aim at providing a brief summary of the crucial influence of major adipokines on the formation and development of vascular calcification, which may contribute to better understanding these adipokines for establishing the appropriate therapeutic strategies to counteract obesity-associated vascular calcification.

TGF-ß signaling and microRNA cross-talk regulates abdominal aortic aneurysm progression.

Abdominal aortic aneurysms (AAA) are permanent and irreversible local dilatations of the abdominal aortic wall. Recent data indicate that the transforming growth factor-beta (TGF-ß) signaling pathway exerts a protective effect on the development of AAA. Some dysregulated microRNAs (miRNA) also appear involved in the expansion of AAA and miRNA-based therapeutics have been shown to effectively inhibit this process. New evidence has revealed that TGF-ß signaling and miRNA interaction may of physiologic and pathophysiologic significance including the progression of AAA. As such, miRNA that regulate TGF-ß signaling may hold promise as potential therapeutic targets. This review explores potential crosstalk between TGF-ß signaling and miRNA in AAA in order improve our understanding of this pathology and explore development of potential therapeutic targets.

The Role of Ubiquitin E3 Ligase in Atherosclerosis.

Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

Role of Kruppel-like factor 4 in atherosclerosis.

Atherosclerosis is one of the chronic progressive diseases, which is caused by vascular injury and promoted by the interaction of various inflammatory factors and inflammatory cells. In recent years, kruppel-like factor 4 (KLF4), a significant transcription factor that participated in cell growth, differentiation and proliferation, has been proved to cause substantial impacts on regulating cardiovascular disease. This paper will give a comprehensive summary to highlight KLF4 as a crucial regulator of foam cell formation, vascular smooth muscle cells (VSMCs) phenotypic transformation, macrophage polarization, endothelial cells inflammation, lymphocyte differentiation and cell proliferation in the process of atherosclerosis. Recent studies show that KLF4 may be an important "molecular switch" in the process of improving vascular injury and inflammation under harmful stimulation, suggesting that KLF4 is a latent disease biomarker for the therapeutic target of atherosclerosis and vascular disease.

Role of PIWI-interacting RNAs on cell survival: Proliferation, apoptosis, and cycle.

PIWI-interacting RNAs (piRNAs) are a kind of non-coding small RNAs, which play a biological role by specifically binding to PIWI proteins. Studies have demonstrated that piRNAs play a significant role in germline cell growth by repressing transposable elements, especially in the regulation of DNA methylation. Recently increasing evidence revealed that piRNAs involved in the regulation of cell proliferation, apoptosis, and cycle; however, the mechanism of piRNAs is unclear. This review summarizes the research progress regarding the roles of piRNAs in the cell proliferation, apoptosis, and cycle.

Intestinal microbiota-farnesoid X receptor axis in metabolic diseases.

Studies have demonstrated that intestinal microbiota is associated with various metabolic diseases including obesity, nonalcoholic fatty liver, and insulin resistance. Farnesoid X receptor (FXR), also known as the bile acid receptor, belongs to the nuclear receptor superfamily, which is involved in the regulation of bile acid, glucose, and lipid metabolism. Researchers have found that intestinal microbiota can regulate FXR activity by affecting bile acid composition, and then regulate the balance of in vivo metabolism. The intestinal microbiota -FXR axis may be an ideal drug target for metabolic diseases. This review summarizes the latest research on the intestinal microbiota /FXR axis, hoping to provide a theoretical basis for further research and clinical application.

SUMOylation in atherosclerosis.

Atherosclerosis (AS) is the pathophysiologic basis of many cardiovascular diseases. A number of studies have shown that post-translational modification (PTM) contributes to the initiation and progression of AS. For example, recent studies found that SUMOylation, ie, small ubiquitin-like modifier (SUMO) conjugation to target substrate proteins, was involved in AS. This PTM appears related to endothelial cell dysfunction (ECD), dyslipidemia and vascular smooth muscle cell (VSMC) proliferation. This review focuses on the molecular effects of SUMOylation in the initiation and progression of AS, including ECD, dyslipidemia and VSMC proliferation to better understand this pathologic process.

S100 proteins in atherosclerosis.

Atherosclerosis is an arterial disease associated with dyslipidemia, abnormal arterial calcification and oxidative stress. It has been shown that a continued chronic inflammatory state of the arterial wall contributes to the development of atherosclerosis. The inflammatory stimulation, recruitment of inflammatory cells and production of pro-inflammatory cytokines enhances vascular inflammation. Some members of the S100 proteins family bind with their receptors, such as advanced glycation end products (RAGE), scavenger receptors (CD36) and toll-like receptor 4 (TLR-4), contributing to the cellular response in atherosclerotic progression. This review summarizes the roles of S100 proteins (S100A8, S100A9 and S100A12) in the vascular inflammation, vascular calcification and vascular oxidative stress. S100 proteins are released from monocytes, smooth muscle cells and endothelial cells in response to cellular stress stimuli, and then the binding of S100 proteins to RAGE activate downstream signaling such as transcription factor kappa B (NF-κB) translocation and reactive oxygen species (ROS) production, which act as a positive feedback loop for inducing pro-inflammatory phenotype in a wide variety of cell types including endothelial cells, vascular smooth muscle cells and leukocytes. Thus, it suggests that the inhibition of S100 proteins-mediated RAGE and TLR4 activation appears to be a promising approach to treat atherosclerosis. In addition, recent study showed that serum S100A12 can predict future cardiovascular events, highlighting that S100A12 is likely to be a potential biomarker of therapeutic efficacy and disease progression in coronary heart disease. Future studies of patients with coronary heart disease may provide more evidences supporting that S100 proteins is promising drug target in the prevention and therapy of atherosclerosis.

Macrophage polarization in atherosclerosis.

Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.