CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation

Particulate ligands including cholesterol crystals and amyloid fibrils induce NLRP3-dependent production of interleukin-1β (IL-1β) in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands including oxidized-LDL, amyloid-β and amylin peptides accumulate in these diseases. Here we identify a CD36-mediated endocytic pathway that coordinates the intracellular conversion of these soluble ligands to crystals or fibrils, resulting in lysosomal disruption and NLRP3-inflammasome activation. Consequently, macrophages lacking CD36 failed to elicit IL-1β production in response to these ligands and targeting CD36 in atherosclerotic mice reduced serum IL-1β and plaque cholesterol crystal accumulation. Collectively, these findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation

Pre-Procedural Atorvastatin Mobilizes Endothelial Progenitor Cells: Clues to the Salutary Effects of Statins on Healing of Stented Human Arteries

OBJECTIVES: Recent clinical trials suggest an LDL-independent superiority of intensive statin therapy in reducing target vessel revascularization and peri-procedural myocardial infarctions in patients who undergo percutaneous coronary interventions (PCI). While animal studies demonstrate that statins mobilize endothelial progenitor cells (EPCs) which can enhance arterial repair and attenuate neointimal formation, the precise explanation for the clinical PCI benefits of high dose statin therapy remain elusive. Thus we serially assessed patients undergoing PCI to test the hypothesis that high dose Atorvastatin therapy initiated prior to PCI mobilizes EPCs that may be capable of enhancing arterial repair. METHODS AND RESULTS: Statin naïve male patients undergoing angiography for stent placement were randomized to standard therapy without Atorvastatin (n = 10) or treatment with Atorvastatin 80 mg (n = 10) beginning three days prior to stent implantation. EPCs were defined by flow cytometry (e.g., surface marker profile of CD45dim/34+/133+/117+). As well, we also enumerated cultured angiogenic cells (CACs) by standard in vitro culture assay. While EPC levels did not fluctuate over time for the patients free of Atorvastatin, there was a 3.5-fold increase in EPC levels with high dose Atorvastatin beginning within 3 days of the first dose (and immediately pre-PCI) which persisted at 4 and 24 hours post-PCI (p<0.05). There was a similar rise in CAC levels as assessed by in vitro culture. CACs cultured in the presence of Atorvastatin failed to show augmented survival or VEGF secretion but displayed a 2-fold increase in adhesion to stent struts (p<0.05). CONCLUSIONS: High dose Atorvastatin therapy pre-PCI improves EPC number and CAC number and function in humans which may in part explain the benefit in clinical outcomes seen in patients undergoing coronary interventions

The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques

Nephrolog

Estrogen Receptor Beta and Atherogenesis: Role of Receptor Related Proteins NM23-H2 and HSP27

There exists an obvious gender disparity in the incidence of cardiovascular disease, with more women over the age of 60 years dying each year compared to their male counterparts. However, pre-menopausal women appear to be spared from developing this disease. Naturally occurring female hormones such as estrogen are thought to provide the cardiovascular system with some form of protection from atherosclerosis. However, the mechanisms behind this protection are poorly understood, and large clinical trials failed to demonstrate any significant cardiovascular benefit for women receiving hormone replacement therapy. Estrogen acts through two primary receptors, ERalpha and ERbeta, and evidence is emerging to suggest that ERbeta is a key mediator of estrogen action in the vessel wall. The objective of this doctoral thesis was to understand more about ERbeta in atherosclerosis by elucidating novel molecular mechanisms of ERbeta action. Two novel proteins were discovered to interact with ERbeta in the vessel wall: (i) non-metastatic protein-23 (NM23-H2) and (ii) heat shock protein 27 (HSP27). The first portion of this study demonstrated that NM23-H2 and ERbeta interact in vascular cells in vitro and NM23-H2 can act as a modest co-activator of estrogen-mediated transcriptional signaling via ERbeta. The expression of NM23-H2 is diminished with progression of atherosclerosis in human coronary arteries, indicating that with advancing disease, the regulation of important estrogen and ERbeta-mediated events may be impaired. The second portion of this study showed that over-expression of HSP27 in a mouse model of atherosclerosis can protect from the development of atherosclerotic lesions, but is dependent on the presence of estrogen. HSP27 release from macrophages is induced by estrogen, where it may serve to protect against atherosclerosis by binding the scavenger receptor-A and preventing the uptake of atherogenic lipoproteins and the ensuing inflammation. The release of this atheroprotective HSP27 is mediated preferentially by ERbeta both in vitro and in vivo, uncovering a novel mechanism of ERbeta-mediated protection in the vessel wall. In summary, this doctoral work reveals two novel ERbeta-associated proteins that can modulate the response to estrogen both in vitro and in vivo, and may be the target of future therapeutics designed to treat and prevent cardiovascular disease in both men and women

Macrophage miRNAs in atherosclerosis

The discovery of endogenous microRNAs (miRNAs) in the early 1990s has been followed by the identification of hundreds of miRNAs and their roles in regulating various biological processes, including proliferation, apoptosis, lipid metabolism, glucose homeostasis and viral infection Esteller (2011), Ameres and Zamore (2013) [1,2]. miRNAs are small (-22 nucleotides) non-coding RNAs that function as "rheostats" to simultaneously tweak the expression of multiple genes within a genetic network, resulting in dramatic functional modulation of biological processes. Although the last decade has brought the identification of miRNAs, their targets and function(s) in health and disease, there remains much to be deciphered from the human genome and its complexities in mechanistic regulation of entire genetic networks. These discoveries have opened the door to new and exciting avenues for therapeutic interventions to treat various pathological diseases, including cardiometabolic diseases such as atherosclerosis, diabetes and obesity. In a complex multi-factorial disease like atherosclerosis, many miRNAs have been shown to contribute to disease progression and may offer novel targets for future therapy. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernandez-Hernando and Yajaira Suarez. (C) 2016 Elsevier B.V. All rights reserved

The walking dead: macrophage inflammation and death in atherosclerosis

To highlight recent studies that describe novel inflammatory and signaling mechanisms that regulate macrophage death in atherosclerosis.Macrophages contribute to all stages of atherosclerosis. The traditional dogma states that in homeostatic conditions, macrophages undergo apoptosis and are efficiently phagocytosed to be cleared by a process called efferocytosis. In advanced atherosclerosis, however, defective efferocytosis results in secondary necrosis of these uncleared apoptotic cells, which ultimately contributes to the formation of the characteristic necrotic core and the vulnerable plaque. Here, we outline the different types of lesional macrophage death: apoptosis, autophagic and the newly defined necroptosis (i.e. a type of programmed necrosis). Recent discoveries demonstrate that macrophage necroptosis directly contributes to necrotic core formation and plaque instability. Further, promoting the resolution of inflammation using preresolving mediators has been shown to enhance efferocytosis and decrease plaque vulnerability. Finally, the canonical 'don't eat me' signal CD47 has recently been described as playing an important role in atherosclerotic lesion progression by impairing efficient efferocytosis. Although we have made significant strides in improving our understanding of cell death and clearance mechanisms in atherosclerosis, there still remains unanswered questions as to how these pathways can be harnessed using therapeutics to promote lesion regression and disease stability.Improving our understanding of the mechanisms that regulate macrophage death in atherosclerosis, in particular apoptosis, necroptosis and efferocytosis, will provide novel therapeutic opportunities to resolve atherosclerosis and promote plaque stability

Unlocking the door to new therapies in cardiovascular disease: microRNAs hold the key

MicroRNAs are the most abundant class of regulatory noncoding RNA and are estimated to regulate over half of all human protein-coding genes. The heart is comprised of some of the most complex and highly conserved genetic networks and is thus under tight regulation by post-transcriptional mechanisms. MicroRNAs (miRNAs) have been found to regulate virtually all aspects of cardiac physiology and pathophysiology, from the development of inflammatory atherosclerosis to hypertrophic remodeling in heart failure. Owing to the wide-spread involvement of miRNAs in the development of and protection from many diseases, there has been increasing excitement surrounding their potential as novel therapeutic targets to treat and prevent the worldwide epidemic of cardiovascular disease