Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the ...degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis.
Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression of autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux upon genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic
mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis.
Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.
Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. ...Using
mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE
/STAT3 axis.
Atherosclerosis, the underlying cause of coronary artery (CAD) and other cardiovascular diseases, is initiated by macrophage-mediated immune responses to lipoprotein and cholesterol accumulation in ...artery walls, which result in the formation of plaques. Unlike at other sites of inflammation, the immune response becomes maladaptive and inflammation fails to resolve. The most common treatment for reducing the risk from atherosclerosis is low density lipoprotein cholesterol (LDL-C) lowering. Studies have shown, however, that while significant lowering of LDL-C reduces the risk of heart attacks to some degree, there is still residual risk for the majority of the population. We and others have observed "residual inflammatory risk" of atherosclerosis after plasma cholesterol lowering in pre-clinical studies, and that this phenomenon is clinically relevant has been dramatically reinforced by the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial. This review will summarize the role of the innate immune system, specifically macrophages, in atherosclerosis progression and regression, as well as the pre-clinical and clinical models that have provided significant insights into molecular pathways involved in the resolution of plaque inflammation and plaque regression. Partnered with clinical studies that can be envisioned in the post-CANTOS period, including progress in developing targeted plaque therapies, we expect that pre-clinical studies advancing on the path summarized in this review, already revealing key mechanisms, will continue to be essential contributors to achieve the goals of dampening plaque inflammation and inducing its resolution in order to maximize the therapeutic benefits of conventional risk factor modifications, such as LDL-C lowering.
Genome wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with the risk of common disorders. However, since the large majority of these ...risk SNPs reside outside gene-coding regions, GWAS generally provide no information about causal mechanisms regarding the specific gene(s) that are affected or the tissue(s) in which these candidate gene(s) exert their effect. The ‘gold standard’ method for understanding causal genes and their mechanisms of action are laborious basic science studies often involving sophisticated knockin or knockout mouse lines, however, these types of studies are impractical as a high-throughput means to understand the many risk variants that cause complex diseases like coronary artery disease (CAD). As a solution, we developed a streamlined, data-driven informatics pipeline to gain mechanistic insights on complex genetic loci. The pipeline begins by understanding the SNPs in a given locus in terms of their relative location and linkage disequilibrium relationships, and then identifies nearby expression quantitative trait loci (eQTLs) to determine their relative independence and the likely tissues that mediate their disease-causal effects. The pipeline then seeks to understand associations with other disease-relevant genes, disease sub-phenotypes, potential causality (Mendelian randomization), and the regulatory and functional involvement of these genes in gene regulatory co-expression networks (GRNs). Here, we applied this pipeline to understand a cluster of SNPs associated with CAD within and immediately adjacent to the gene encoding
HDAC9
. Our pipeline demonstrated, and validated, that this locus is causal for CAD by modulation of
TWIST1
expression levels in the arterial wall, and by also governing a GRN related to metabolic function in skeletal muscle. Our results reconciled numerous prior studies, and also provided clear evidence that this locus does not govern HDAC9 expression, structure or function. This pipeline should be considered as a powerful and efficient way to understand GWAS risk loci in a manner that better reflects the highly complex nature of genetic risk associated with common disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose of review
Spontaneous and isolated visceral artery dissections (VAD) are rare but potentially life-threatening conditions that occur when there is a tear or separation of the inner lining of ...the blood vessels that supply the organs of the abdomen. This includes the celiac artery, superior mesenteric artery (SMA), and renal arteries leading to ischemia and infarction of the affected organs. We will discuss the natural history of VAD and management options with a focus on recent literature.
Recent findings
Recent case series and meta-analyses indicate that VAD is a condition with overall low mortality that can be managed conservatively with observation, antiplatelet therapy, and/or anticoagulation. Few patients will require revascularization via endovascular and surgical intervention. Additionally, emerging data suggests that systematic imaging to evaluate for multiple artery aneurysm, dissection, and/or fibromuscular dysplasia (FMD) may help to prognosticate the patient’s risk for additional dissection events or identify those that will benefit from further evaluation with genetic testing for heritable arteriopathy.
Summary
For a majority of VAD patients, the available data suggest that symptoms resolve and dissections heal with medical management alone. In cases of on-going ischemia or symptoms, revascularization can be done safely and effectively. Patients should undergo evaluation for other signs and symptoms of systemic arteriopathy with imaging, and if appropriate genetic testing for heritable arteriopathies.
Takotsubo Cardiomyopathy in COVID-19 Giustino, Gennaro; Croft, Lori B.; Oates, Connor P. ...
Journal of the American College of Cardiology,
08/2020, Letnik:
76, Številka:
5
Journal Article
Matrices often represent important information in scientific applications and are involved in performing complex calculations. But systematically testing these applications is hard due to the oracle ...problem. Metamorphic testing is an effective approach to test such applications because it uses metamorphic relations to determine whether test cases have passed or failed. Metamorphic relations are typically identified with the help of a domain expert and is a labor intensive task. In this work we use a graph kernel based machine learning approach to predict metamorphic relations for matrix calculation programs. Previously, this graph kernel based machine learning approach was used to successfully predict metamorphic relations for programs that perform numerical calculations. Results of this study show that this approach can be used to predict metamorphic relations for matrix calculation programs as well.
RATIONALE:Regression of atherosclerosis is an important clinical goal; however, the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. ...Regulatory T cells (Tregs) have been shown to be atheroprotective, yet the numbers of these immunosuppressive cells decrease with disease progression, and whether they contribute to atherosclerosis regression is not known.
OBJECTIVE:We investigated the roles of Tregs in the resolution of atherosclerotic inflammation, tissue remodeling, and plaque contraction during atherosclerosis regression.
METHODS AND RESULTS:Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. Single-cell RNA-sequencing of plaque immune cells revealed that unlike Tregs from progressing plaques that expressed markers of natural Tregs derived from the thymus, Tregs in regressing plaques lacked Nrp1 expression, suggesting that they are induced in the periphery during lipid-lowering therapy. To test whether Tregs are required for resolution of atherosclerotic inflammation and plaque regression, Tregs were depleted using CD25 monoclonal antibody in atherosclerotic mice during apolipoprotein B antisense oligonucleotide-mediated lipid lowering. Morphometric analyses revealed that Treg depletion blocked plaque remodeling and contraction, and impaired hallmarks of inflammation resolution, including dampening of the T helper 1 response, alternative activation of macrophages, efferocytosis, and upregulation of specialized proresolving lipid mediators.
CONCLUSIONS:Our data establish essential roles for Tregs in resolving atherosclerotic cardiovascular disease and provide mechanistic insight into the pathways governing plaque remodeling and regression of disease.
Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity
or surgery
, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be ...at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors
. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6C
monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6C
monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.
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