Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner.

AIMS: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signaling in atherosclerosis. METHODS AND RESULTS: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1 deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on estrogen receptor (ER)α-estradiol signaling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing and mitochondrial respiration among the key processes affected by CB1 signaling, which was supported by metabolic flux assays. Chronic administration of the peripherally-restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology. CONCLUSION: Impaired macrophage CB1 signaling is atheroprotective by limiting their arterial recruitment, proliferation and inflammatory reprogramming in male mice. The importance of macrophage CB1 signaling appears to be sex-dependent.

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis.

Circulating low-density lipoprotein (LDL) levels are a major risk factor for cardiovascular diseases (CVD), and even though current treatment strategies focusing on lowering lipid levels are effective, CVD remains the primary cause of death worldwide. Atherosclerosis is the major cause of CVD and is a chronic inflammatory condition in which various cell types and protein kinases play a crucial role. However, the underlying mechanisms of atherosclerosis are not entirely understood yet. Notably, protein kinases are highly druggable targets and represent, therefore, a novel way to target atherosclerosis. In this review, the potential role of the calcium/calmodulin-dependent protein kinase-like (CaMKL) family and its role in atherosclerosis will be discussed. This family consists of 12 subfamilies, among which are the well-described and conserved liver kinase B1 (LKB1) and 5' adenosine monophosphate-activated protein kinase (AMPK) subfamilies. Interestingly, LKB1 plays a key role and is considered a master kinase within the CaMKL family. It has been shown that LKB1 signaling leads to atheroprotective effects, while, for example, members of the microtubule affinity-regulating kinase (MARK) subfamily have been described to aggravate atherosclerosis development. These observations highlight the importance of studying kinases and their signaling pathways in atherosclerosis, bringing us a step closer to unraveling the underlying mechanisms of atherosclerosis.

ITIH5 as a multifaceted player in pancreatic cancer suppression, impairing tyrosine kinase signaling, cell adhesion and migration.

Inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5) has been identified as a metastasis suppressor gene in pancreatic cancer. Here, we analyzed ITIH5 promoter methylation and protein expression in The Cancer Genome Atlas (TCGA) dataset and three tissue microarray cohorts (n = 618), respectively. Cellular effects, including cell migration, focal adhesion formation and protein tyrosine kinase activity, induced by forced ITIH5 expression in pancreatic cancer cell lines were studied in stable transfectants. ITIH5 promoter hypermethylation was associated with unfavorable prognosis, while immunohistochemistry demonstrated loss of ITIH5 in the metastatic setting and worsened overall survival. Gain-of-function models showed a significant reduction in migration capacity, but no alteration in proliferation. Focal adhesions in cells re-expressing ITIH5 exhibited a smaller and more rounded phenotype, typical for slow-moving cells. An impressive increase of acetylated alpha-tubulin was observed in ITIH5-positive cells, indicating more stable microtubules. In addition, we found significantly decreased activities of kinases related to focal adhesion. Our results indicate that loss of ITIH5 in pancreatic cancer profoundly affects its molecular profile: ITIH5 potentially interferes with a variety of oncogenic signaling pathways, including the PI3K/AKT pathway. This may lead to altered cell migration and focal adhesion formation. These cellular alterations may contribute to the metastasis-inhibiting properties of ITIH5 in pancreatic cancer.

ADAM10 and ADAM17, Major Regulators of Chronic Kidney Disease Induced Atherosclerosis?

Chronic kidney disease (CKD) is a major health problem, affecting millions of people worldwide, in particular hypertensive and diabetic patients. CKD patients suffer from significantly increased cardiovascular disease (CVD) morbidity and mortality, mainly due to accelerated atherosclerosis development. Indeed, CKD not only affects the kidneys, in which injury and maladaptive repair processes lead to local inflammation and fibrosis, but also causes systemic inflammation and altered mineral bone metabolism leading to vascular dysfunction, calcification, and thus, accelerated atherosclerosis. Although CKD and CVD individually have been extensively studied, relatively little research has studied the link between both diseases. This narrative review focuses on the role of a disintegrin and metalloproteases (ADAM) 10 and ADAM17 in CKD and CVD and will for the first time shed light on their role in CKD-induced CVD. By cleaving cell surface molecules, these enzymes regulate not only cellular sensitivity to their micro-environment (in case of receptor cleavage), but also release soluble ectodomains that can exert agonistic or antagonistic functions, both locally and systemically. Although the cell-specific roles of ADAM10 and ADAM17 in CVD, and to a lesser extent in CKD, have been explored, their impact on CKD-induced CVD is likely, yet remains to be elucidated.

Endothelial ADAM10 controls cellular response to oxLDL and its deficiency exacerbates atherosclerosis with intraplaque hemorrhage and neovascularization in mice.

Introduction: The transmembrane protease A Disintegrin And Metalloproteinase 10 (ADAM10) displays a "pattern regulatory function," by cleaving a range of membrane-bound proteins. In endothelium, it regulates barrier function, leukocyte recruitment and angiogenesis. Previously, we showed that ADAM10 is expressed in human atherosclerotic plaques and associated with neovascularization. In this study, we aimed to determine the causal relevance of endothelial ADAM10 in murine atherosclerosis development in vivo. Methods and results: Endothelial Adam10 deficiency (Adam10 ecko ) in Western-type diet (WTD) fed mice rendered atherogenic by adeno-associated virus-mediated PCSK9 overexpression showed markedly increased atherosclerotic lesion formation. Additionally, Adam10 deficiency was associated with an increased necrotic core and concomitant reduction in plaque macrophage content. Strikingly, while intraplaque hemorrhage and neovascularization are rarely observed in aortic roots of atherosclerotic mice after 12 weeks of WTD feeding, a majority of plaques in both brachiocephalic artery and aortic root of Adam10ecko mice contained these features, suggestive of major plaque destabilization. In vitro, ADAM10 knockdown in human coronary artery endothelial cells (HCAECs) blunted the shedding of lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) and increased endothelial inflammatory responses to oxLDL as witnessed by upregulated ICAM-1, VCAM-1, CCL5, and CXCL1 expression (which was diminished when LOX-1 was silenced) as well as activation of pro-inflammatory signaling pathways. LOX-1 shedding appeared also reduced in vivo, as soluble LOX-1 levels in plasma of Adam10ecko mice was significantly reduced compared to wildtypes. Discussion: Collectively, these results demonstrate that endothelial ADAM10 is atheroprotective, most likely by limiting oxLDL-induced inflammation besides its known role in pathological neovascularization. Our findings create novel opportunities to develop therapeutics targeting atherosclerotic plaque progression and stability, but at the same time warrant caution when considering to use ADAM10 inhibitors for therapy in other diseases.

Sex-specific and hormone-related differences in vascular remodelling in atherosclerosis.

Atherosclerosis, a lipid-driven inflammatory disease, is the main underlying cause of cardiovascular diseases (CVDs) both in men and women. Sex-related dimorphisms regarding CVDs and atherosclerosis were observed since more than a decade ago. Inflammatory mediators such as cytokines, but also endothelial dysfunction, vascular smooth muscle cell migration and proliferation lead to vascular remodelling but are differentially affected by sex. Each year a greater number of men die of CVDs compared with women and are also affected by CVDs at an earlier age (40-70 years old) while women develop atherosclerosis-related complications mainly after menopause (60+ years). The exact biological reasons behind this discrepancy are still not well-understood. From the numerous animal studies on atherosclerosis, only a few include both sexes and even less investigate and highlight the sex-specific differences that may arise. Endogenous sex hormones such as testosterone and oestrogen modulate the atherosclerotic plaque composition and the frequency of such plaques. In men, testosterone seems to act like a double-edged sword as its decrease with ageing correlates with an increased risk of atherosclerotic CVDs, while testosterone is also reported to promote inflammatory immune cell recruitment into the atherosclerotic plaque. In premenopausal women, oestrogen exerts anti-atherosclerotic effects, which decline together with its level after menopause resulting in increased CVD risk in ageing women. However, the interplay of sex hormones, sex-specific immune responses and other sex-related factors is still incompletely understood. This review highlights reported sex differences in atherosclerotic vascular remodelling and the role of endogenous sex hormones in this process.

Endothelial ACKR3 drives atherosclerosis by promoting immune cell adhesion to vascular endothelium.

Atherosclerosis is the foundation of potentially fatal cardiovascular diseases and it is characterized by plaque formation in large arteries. Current treatments aimed at reducing atherosclerotic risk factors still allow room for a large residual risk; therefore, novel therapeutic candidates targeting inflammation are needed. The endothelium is the starting point of vascular inflammation underlying atherosclerosis and we could previously demonstrate that the chemokine axis CXCL12-CXCR4 plays an important role in disease development. However, the role of ACKR3, the alternative and higher affinity receptor for CXCL12 remained to be elucidated. We studied the role of arterial ACKR3 in atherosclerosis using western diet-fed Apoe-/- mice lacking Ackr3 in arterial endothelial as well as smooth muscle cells. We show for the first time that arterial endothelial deficiency of ACKR3 attenuates atherosclerosis as a result of diminished arterial adhesion as well as invasion of immune cells. ACKR3 silencing in inflamed human coronary artery endothelial cells decreased adhesion molecule expression, establishing an initial human validation of ACKR3's role in endothelial adhesion. Concomitantly, ACKR3 silencing downregulated key mediators in the MAPK pathway, such as ERK1/2, as well as the phosphorylation of the NF-kB p65 subunit. Endothelial cells in atherosclerotic lesions also revealed decreased phospho-NF-kB p65 expression in ACKR3-deficient mice. Lack of smooth muscle cell-specific as well as hematopoietic ACKR3 did not impact atherosclerosis in mice. Collectively, our findings indicate that arterial endothelial ACKR3 fuels atherosclerosis by mediating endothelium-immune cell adhesion, most likely through inflammatory MAPK and NF-kB pathways.

The gut hormone glucose-dependent insulinotropic polypeptide is downregulated in response to myocardial injury.

BACKGROUND: The gut incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following food intake leading to insulin secretion and glucose lowering. Beyond its metabolic function GIP has been found to exhibit direct cardio- and atheroprotective effects in mice and to be associated with cardiovascular prognosis in patients with myocardial infarction. The aim of this study was to characterize endogenous GIP levels in patients with acute myocardial infarction. METHODS AND RESULTS: Serum concentrations of GIP were assessed in 731 patients who presented with clinical indication of coronary angiography. Circulating GIP levels were significantly lower in patients with STEMI (ST-elevation myocardial infarction; n=100) compared to clinically stable patients without myocardial infarction (n=631) (216.82 pg/mL [Q1-Q3: 52.37-443.07] vs. 271.54 pg/mL [Q1-Q3: 70.12-542.41], p = 0.0266). To characterize endogenous GIP levels in patients with acute myocardial injury we enrolled 18 patients scheduled for cardiac surgery with cardiopulmonary bypass and requirement of extracorporeal circulation as a reproducible condition of myocardial injury. Blood samples were drawn directly before surgery (baseline), upon arrival at the intensive care unit (ICU), 6 h post arrival to the ICU and at the morning of the first and second postoperative days. Mean circulating GIP concentrations decreased in response to surgery from 45.3 ± 22.6 pg/mL at baseline to a minimum of 31.9 ± 19.8 pg/mL at the first postoperative day (p = 0.0384) and rose again at the second postoperative day (52.1 ± 28.0 pg/mL). CONCLUSIONS: Circulating GIP levels are downregulated in patients with myocardial infarction and following cardiac surgery. These results might suggest nutrition-independent regulation of GIP secretion following myocardial injury in humans.

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin.

BACKGROUND: Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation. METHODS: Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca2+]i, aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed. RESULTS: Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca2+ elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation. CONCLUSION: Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.

PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo.

Proprotein convertase subtilin/kexin type 9 (PCSK9) is a protease secreted mainly by hepatocytes and in lesser quantities by intestines, pancreas, and vascular cells. Over the years, this protease has gained importance in the field of cardiovascular biology due to its regulatory action on the low-density lipoprotein receptor (LDLR). However, recently, it has also been shown that PCSK9 acts independent of LDLR to cause vascular inflammation and increase the severity of several cardiovascular disorders. We hypothesized that PCSK9 affects the expression of chemokine receptors, major mediators of inflammation, to influence cardiovascular health. However, using overexpression of PCSK9 in murine models in vivo and PCSK9 stimulation of myeloid and vascular cells in vitro did not reveal influences of PCSK9 on the expression of certain chemokine receptors that are known to be involved in the development and progression of atherosclerosis and vascular inflammation. Hence, we conclude that the inflammatory effects of PCSK9 are not associated with the here investigated chemokine receptors and additional research is required to elucidate which mechanisms mediate PCSK9 effects independent of LDLR.

Targeting the chemokine network in atherosclerosis.

Chemokines and their receptors represent a potential target for immunotherapy in chronic inflammation. They comprise a large family of cytokines with chemotactic activity, and their cognate receptors are expressed on all cells of the body. This network dictates leukocyte recruitment and activation, angiogenesis, cell proliferation and maturation. Dysregulation of chemokine and chemokine receptor expression as well as function participates in many pathologies including cancer, autoimmune diseases and chronic inflammation. In atherosclerosis, a lipid-driven chronic inflammation of middle-sized and large arteries, chemokines and their receptors participates in almost all stages of the disease from initiation of fatty streaks to mature atherosclerotic plaque formation. Atherosclerosis and its complications are the main driver of mortality and morbidity in cardiovascular diseases (CVD). Hence, exploring new fields of therapeutic targeting of atherosclerosis is of key importance. This review gives an overview of the recent advances on the role of key chemokines and chemokine receptors in atherosclerosis, addresses chemokine-based biomarkers at biochemical, imaging and genetic level in human studies, and highlights the clinial trials targeting atherosclerosis.

Transcriptome signature of miRNA-26b KO mouse model suggests novel targets.

BACKGROUND: MicroRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. One of the miRNAs that has been shown to play a role in various pathologies like cancer, neurological disorders and cardiovascular diseases is miRNA-26b. However, these studies only demonstrated rather ambiguous associations without revealing a causal relationship. Therefore, the aim of this study is to establish and validate a mouse model which enables the elucidation of the exact role of miRNA-26b in various pathologies. RESULTS: A miRNA-26b-deficient mouse model was established using homologous recombination and validated using PCR. miRNA-26b-deficient mice did not show any physiological abnormalities and no effects on systemic lipid levels, blood parameters or tissue leukocytes. Using next generation sequencing, the gene expression patterns in miRNA-26b-deficient mice were analyzed and compared to wild type controls. This supported the already suggested role of miRNA-26b in cancer and neurological processes, but also revealed novel associations of miRNA-26b with thermogenesis and allergic reactions. In addition, detailed analysis identified several genes that seem to be highly regulated by miRNA-26b, which are linked to the same pathological conditions, further confirming the role of miRNA-26b in these pathologies and providing a strong validation of our mouse model. CONCLUSIONS: miRNA-26b plays an important role in various pathologies, although causal relationships still have to be established. The described mouse model of miRNA-26b deficiency is a crucial first step towards the identification of the exact role of miRNA-26b in various diseases that could identify miRNA-26b as a promising novel diagnostic or even therapeutic target in a broad range of pathologies.

Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health.

The calcium Sensing Receptor (CaSR) is a cell surface receptor belonging to the family of G-protein coupled receptors. CaSR is mainly expressed by parathyroid glands, kidneys, bone, skin, adipose tissue, the gut, the nervous system, and the cardiovascular system. The receptor, as its name implies is involved in sensing calcium fluctuations in the extracellular matrix of cells, thereby having a major impact on the mineral homeostasis in humans. Besides calcium ions, the receptor is also activated by other di- and tri-valent cations, polypeptides, polyamines, antibiotics, calcilytics and calcimimetics, which upon binding induce intracellular signaling pathways. Recent studies have demonstrated that CaSR influences a wide variety of cells and processes that are involved in inflammation, the cardiovascular system, such as vascular calcification, atherosclerosis, myocardial infarction, hypertension, and obesity. Therefore, in this review, the current understanding of the role that CaSR plays in inflammation and its consequences on the cardiovascular system will be highlighted.

High-Density Lipoproteins and Apolipoprotein A1.

High-density lipoprotein (HDL) and its main protein component apolipoprotein (apo)A-I, play an important role in cholesterol homeostasis. It has been demonstrated that HDLs comprise of a very heterogeneous group of particles, not only regarding size but also composition. HDL's best described function is its role in the reverse cholesterol transport, where lipid-free apoA-I or small HDLs can accept and take up cholesterol from peripheral cells and subsequently transport this to the liver for excretion. However, several other functions have also been described, like anti-oxidant, anti-inflammatory and anti-thrombotic effects. In this article, the general features, synthesis and metabolism of apoA-I and HDLs will be discussed. Additionally, an overview of HDL functions will be given, especially in the context of some major pathologies like cardiovascular disease, cancer and diabetes mellitus. Finally, the therapeutic potential of raising HDL will be discussed, focussing on the difficulties of the past and the promises of the future.

The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice.

Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient (Ldlr-/- ) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONV-R). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF Ldlr-/- mice and CONV-R Ldlr-/- mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R Ldlr-/- mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF Ldlr-/- mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF Ldlr-/- mice on HFD were diminished compared to CONV-R Ldlr-/- controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF Ldlr-/- mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF Ldlr-/- mice relative to CONV-R Ldlr-/- mice. Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF Ldlr-/- mice on type III collagen.IMPORTANCE Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr-/- mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions.

Hematopoietic ChemR23 (Chemerin Receptor 23) Fuels Atherosclerosis by Sustaining an M1 Macrophage-Phenotype and Guidance of Plasmacytoid Dendritic Cells to Murine Lesions-Brief Report.

Objective- Expression of the chemokine-like receptor ChemR23 (chemerin receptor 23) has been specifically attributed to plasmacytoid dendritic cells (pDCs) and macrophages and ChemR23 has been suggested to mediate an inflammatory immune response in these cells. Because chemokine receptors are important in perpetuating chronic inflammation, we aimed to establish the role of ChemR23-deficiency on macrophages and pDCs in atherosclerosis. Approach and Results- ChemR23-knockout/knockin mice expressing eGFP (enhanced green fluorescent protein) were generated and after crossing with apolipoprotein E-deficient ( Apoe-/- ChemR23 e/e) animals were fed a western-type diet for 4 and 12 weeks. Apoe-/- ChemR23 e/e mice displayed reduced lesion formation and reduced leukocyte adhesion to the vessel wall after 4 weeks, as well as diminished plaque growth, a decreased number of lesional macrophages with an increased proportion of M2 cells and a less inflammatory lesion composition after 12 weeks of western-type diet feeding. Hematopoietic ChemR23-deficiency similarly reduced atherosclerosis. Additional experiments revealed that ChemR23-deficiency induces an alternatively activated macrophage phenotype, an increased cholesterol efflux and a systemic reduction in pDC frequencies. Consequently, expression of the pDC marker SiglecH in atherosclerotic plaques of Apoe-/- ChemR23 e/e mice was declined. ChemR23-knockout pDCs also exhibited a reduced migratory capacity and decreased CCR (CC-type chemokine receptor)7 expression. Finally, adoptive transfer of sorted wild-type and knockout pDCs into Apoe-/- recipient mice revealed reduced accumulation of ChemR23-deficient pDCs in atherosclerotic lesions. Conclusions- Hematopoietic ChemR23-deficiency increases the proportion of alternatively activated M2 macrophages in atherosclerotic lesions and attenuates pDC homing to lymphatic organs and recruitment to atherosclerotic lesions, which synergistically restricts atherosclerotic plaque formation and progression.