Progression of Multifaceted Immune Cells in Atherosclerotic Development

Atherosclerosis is a major cause of morbidity and mortality due to cardiovascular diseases, such as coronary artery disease, stroke, and peripheral vascular disease, that are associated with thrombosis-induced organ infarction. In Westernized countries, the high prevalence of obesity-induced insulin resistance is predicted to be a major factor leading to atherosclerotic vascular disease. Both genetic and environmental factors interfere with immune responses in atherosclerosis development with chronic and non-resolving states. The most known autoimmune disease therapy is cytokine-targeted therapy, which targets tumor necrosis factor-α and interleukin (IL)-17 antagonists. Recently, a clinical trial with the anti-IL-1β antibody (canakinumab) had shown that the anti-inflammatory effects in canakinumab-treated subjects play a critical role in reducing cardiovascular disease prevalence. Recent emerging data have suggested effective therapeutics involving anti-obesity and anti-diabetic agents, as well as statin and anti-platelet drugs, for atherothrombosis prevention. It is well-known that specialized immune differentiation and activation completely depends on metabolic reprogramming mediated by mitochondrial dynamics in distinct immune cells. Therefore, there is a strong mechanistic link between metabolism and immune function mediated by mitochondrial function. In this review, we describe that cellular metabolism in immune cells is strongly interconnected with systemic metabolism in terms of diverse phenotypes and activation.

Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism

Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.

Scoparone interferes with STAT3-induced proliferation of vascular smooth muscle cells

Scoparone, which is a major constituent of Artemisia capillaries, has been identified as an anticoagulant, hypolipidemic, vasorelaxant, anti-oxidant and anti-inflammatory drug, and it is used for the traditional treatment of neonatal jaundice. Therefore, we hypothesized that scoparone could suppress the proliferation of VSMCs by interfering with STAT3 signaling. We found that the proliferation of these cells was significantly attenuated by scoparone in a dose-dependent manner. Scoparone markedly reduced the serum-stimulated accumulation of cells in the S phase and concomitantly increased the proportion of cells in the G0/G1 phase, which was consistent with the reduced expression of cyclin D1, phosphorylated Rb and survivin in the VSMCs. Cell adhesion markers, such as MCP-1 and ICAM-1, were significantly reduced by scoparone. Interestingly, this compound attenuated the increase in cyclin D promoter activity by inhibiting the activities of both the WT and active forms of STAT3. Similarly, the expression of a cell proliferation marker induced by PDGF was decreased by scoparone with no change in the phosphorylation of JAK2 or Src. On the basis of the immunofluorescence staining results, STAT3 proteins phosphorylated by PDGF were predominantly localized to the nucleus and were markedly reduced in the scoparone-treated cells. In summary, scoparone blocks the accumulation of STAT3 transported from the cytosol to the nucleus, leading to the suppression of VSMC proliferation through G1 phase arrest and the inhibition of Rb phosphorylation. This activity occurs independent of the form of STAT3 and upstream of kinases, such as Jak and Src, which are correlated with abnormal vascular remodeling due to the presence of an excess of growth factors following vascular injury. These data provide convincing evidence that scoparone may be a new preventative agent for the treatment of cardiovascular diseases.