Abstract-The role of hepatic lipase as a multifunctional protein that modulates lipoprotein metabolism and atherosclerosis has been extensively documented over the last decade. Hepatic lipase functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Hepatic lipase also serves as a ligand that facilitates lipoprotein uptake by cell surface receptors and proteoglycans, thereby directly affecting cellular lipid delivery. Recently, another process by which hepatic lipase modulates atherogenic risk has been identified. Bone marrow transplantation studies demonstrate that hepatic lipase present in aortic lesions markedly alters aortic lesion formation even in the absence of changes in plasma lipids. These multiple functions of hepatic lipase, which facilitate not only plasma lipid metabolism but also cellular lipid uptake, can be anticipated to have a major and complex impact on atherogenesis. Consistently, human and animal studies support proatherogenic and antiatherogenic roles for hepatic lipase. Key Words: transgenic mouse models Ⅲ lipolytic enzyme Ⅲ ligand-binding function Ⅲ macrophages Ⅲ bone marrow transplantation Ⅲ aortic atherosclerosis C oronary artery disease (CAD) is a major cause of mortality in advanced societies. 1-3 Multiple factors contribute to the formation of lesions that ultimately lead to CAD. One of the initial events in the development of atherosclerosis is the accumulation of cells containing excess lipids within the arterial wall. 4 Plasma lipoproteins play a major role in the deposition and removal of lipids that accumulate in atherosclerotic lesions. Apolipoprotein B (apoB)-containing lipoproteins and high-density lipoprotein (HDL) have opposite effects on CAD and are independent risk factors for this disease. [5][6][7] Both classes of lipoproteins have been major targets for the development of new therapeutic approaches for treatment of CAD.During the last decade, a great deal of interest has focused on hepatic lipase and its impact on lipoprotein metabolism, including intermediate-density lipoproteins (IDLs), chylomicron remnants and HDLs, and atherogenesis. Hepatic lipase has been shown in several studies to modulate atherogenic risk; however, its role as either a protective or proatherogenic agent remains unclear. Published human and animal studies support proatherogenic and antiatherogenic functions for hepatic lipase. 8 -14 In humans, low hepatic lipase activity has been associated with increased risk of CAD. [15][16][17][18] Furthermore, premature CAD has been reported in patients with complete hepatic lipase deficiency, 19 although the manner in which these very few individuals have been identified raises the issue of ascertainment bias. Other studies have concluded that decreased hepatic lipase activity does not influence susceptibility to CAD. 20 Finally, increased hepatic lipase activity has been reported in patients with CAD. 21,22 A proatherogenic role for hepatic lipase has been suggested from the inverse corre...

SUMMARY Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1β production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.

Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.

Our findings establish a direct link between p19(ARF), plaque apoptosis, and atherosclerosis, and suggest that human genetic variants associated to diminished CDKN2A expression may accelerate atherosclerosis by limiting plaque apoptosis.

Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction.

Objective: Abdominal aortic aneurysm (AAA) is a pathological condition of permanent vessel dilatation that predisposes to the potentially fatal consequence of aortic rupture. SGLT-2 (sodium-glucose cotransporter 2) inhibitors have emerged as powerful pharmacological tools for type 2 diabetes mellitus treatment. Beyond their glucose-lowering effects, recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events and have beneficial effects on several vascular diseases such as atherosclerosis; however, the potential effects of SGLT-2 inhibition on AAA remain unknown. This study evaluates the effect of oral chronic treatment with empagliflozin—an SGLT-2 inhibitor—on dissecting AAA induced by Ang II (angiotensin II) infusion in apoE (apolipoprotein E) −/ − mice. Approach and Results: Empagliflozin treatment significantly reduced the Ang II–induced increase in maximal suprarenal aortic diameter in apoE −/ − mice independently of blood pressure effects. Immunohistochemistry analysis revealed that empagliflozin diminished Ang II–induced elastin degradation, neovessel formation, and macrophage infiltration at the AAA lesion. Furthermore, Ang II infusion resulted in a marked increase in the expression of chemokines (CCL-2 [chemokine (C-C motif) ligand 2] and CCL-5 [chemokine (C-C motif) ligand 5]), VEGF (vascular endothelial growth factor), and MMP (matrix metalloproteinase)-2 and MMP-9 in suprarenal aortic walls of apoE −/ − mice, and all were reduced by empagliflozin cotreatment. Western blot analysis revealed that p38 MAPK (p38 mitogen-activated protein kinase) and NF-κB (nuclear factor-κB) activation was also reduced in the suprarenal aortas of apoE −/ − mice cotreated with empagliflozin. Finally, in vitro studies in human aortic endothelial cells and macrophages showed that empagliflozin inhibited leukocyte-endothelial cell interactions and release of proinflammatory chemokines. Conclusions: Pharmacological inhibition of SGLT-2 by empagliflozin inhibits AAA formation. SGLT-2 inhibition might represent a novel promising therapeutic strategy to prevent AAA progression.

Excessive hyperplastic cell growth within occlusive vascular lesions has been recognized as a key component of the inflammatory response associated with atherosclerosis, restenosis post-angioplasty, and graft atherosclerosis after coronary artery bypass. Understanding the molecular mechanisms that regulate arterial cell proliferation is therefore essential for the development of new tools for the treatment of these diseases. Mammalian cell proliferation is controlled by a large number of proteins that modulate the mitotic cell cycle, including cyclin-dependent kinases, cyclins, and tumour suppressors. The purpose of this review is to summarize current knowledge about the role of these cell cycle regulators in the development of native and graft atherosclerosis that has arisen from animal studies, histological examination of specimens from human patients, and genetic studies.

Lixisenatide decreases atheroma plaque size and instability in Apoe Irs2 mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance.