SFB 1123 Atherosclerosis-Mechanisms and Networks of Novel Therapeutic Targets

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Projects Area B: Nucleic acids and lipid mediators

B02: Dissection of NO-cGMP-signaling in coronary artery disease

Several loci which harbor genes of the NO-cGMP-signaling pathway have been genome-wide significantly associated with coronary artery disease (CAD) and myocardial infarction. While the molecular mechanisms affecting the GUCY1A3 locus have been resolved this remains unclear for variants at the loci which encode endothelial nitric oxide synthase (NOS3) and phosphodiesterase 5A (PDE5A). Here, we aim to specifically investigate the link between genotype and phenotype at the NOS3 locus (Aim 1), to elucidate the role of PDE5A in modulating CAD risk (Aim 2), and to evaluate strategies for therapeutic targeting the pathway in in vitro and in vivo models (Aim 3).

B03: Mechanistic Role of HDAC9 in Atherosclerosis

Our previous work established a pro-inflammatory and pro-atherogenic role of HDAC9 and identified an activating effect of HDAC9 on NF-κB signaling. We now aim to expand on these results by addressing the following: (Aim 1) examine effects of HDAC9 on chromatin accessibility, the transcriptome, as well as the cellular proteome and secretome using ATAC-seq, RNA-seq, and LC-MS/MS; (Aim 2) investigate HDAC9-related alterations in NF-κB signaling under pro-inflammatory conditions; (Aim 3) study cell-specific effects of HDAC9 on atheroprogression and neointima formation using Hdac9flox/flox and atherogenic deleter mice.

topB04: miRNA-regulated energy metabolism in macrophage-derived foam cells

Excessive lipid storage in macrophages is regulated by miRNAs and results in the formation of foam cells, which eventually undergo apoptosis and contribute decisively to the necrotic core in atherosclerotic lesions. We hypothesize that miRNAs control foam cell formation by regulating the metabolism of triglycerides. Thus, we will study whether Dicer limits foam cell formation by increasing fatty acid oxidation (Aim 1), investigate the mechanism by which miR-147 regulates energy metabolism in foam cells (Aim 2), and test whether let-7b expression in macrophages reduces foam cell formation and atherosclerosis by enhancing oxidative phosphorylation (Aim 3).

B05: Neutrophil-borne miRNAs control atherosclerosis

Activation of SMCs and macrophages is important in advanced atherosclerosis. A screen of miRNAs embedded within neutrophil extracellular traps (NETs) revealed the targeted deposition of several miRNAs with relevance to macrophage and SMC activity. To dissect the importance of neutrophil miRNAs, we will study the intrinsic impact of these on neutrophil functionality (Aim 1) and investigate how NET-bound miRNAs alter the functionality of macrophages and SMC (Aim 2). Finally, we will study the contribution of neutrophil-borne miRNAs to atheroprogression and use intervention approaches to abrogate deregulated processes initiated by neutrophil miRNAs (Aim 3).

B06: Immune cell control of plaque-triggered thrombosis – impact of aging

Innate immune cells contribute to atherothrombosis. Yet, how aging impacts on the pro- and antithrombotic action of innate immune cells remains incompletely understood. We therefore plan to identify and compare the inflammatory pathways that support and suppress atherothrombosis in young and aged atherosclerotic mice (Aim 1). We will dissect the role of immune cell pathways controlled by mTORC1 activity and autophagy induction, processes that altogether affect aging (Aim 2). Finally, we will investigate how necrotic core components are sensed and engulfed by recruited immune cells during atherothrombosis in young and aged mice (Aim 3).to

B09: Role of peripheral CB1 cannabinoid receptors in atherosclerosis and metabolism

In view of potential therapeutic application of peripherally active cannabinoid receptor CB1 antagonists, we aim to clarify cell-specific effects of vascular and hematopoietic CB1 in atherosclerosis. So far, our data suggest opposing roles of endothelial and myeloid CB1 in atherosclerotic plaque formation, with surprising effects on metabolic parameters in absence of endothelial CB1. In the following, we aim to address how endothelial CB1 promotes atheroprogression (Aim 1) and affects metabolic parameters (Aim 2). In addition, we will investigate how macrophage CB1 signaling affects atherosclerotic plaque stability (Aim 3).

B10: Role of the cholesterol sensor Nfe21I1 in adipose inflammation and atherogenesis

Atherosclerosis is associated with perivascular inflammation, which is a powerful predictor for cardiac mortality. However, whether adipocyte-derived inflammatory mediators causally drive atherosclerosis remains ill-defined. In this project, we will define the role of adipocyte Nfe2l1, a cholesterol-sensing transcription factor that regulates proteostasis. By studying cultured adipocytes, preclinical transgenic mouse models, as well as human adipose and atheroma samples, we will define the translational significance of Nfe2l1 for adipose inflammation and atherosclerosis.

B11: Inflammation begets inflammation – impact of remote injuries on atherosclerosis progression

We identified in our collaborative preliminary work that sterile injuries such as ischemic stroke (IS) and myocardial infarction (MI) lead to the destabilization of vulnerable atherosclerotic plaques and recurrent ischemic events. However, the exact mechanisms underlying secondary plaque rupture after remote organ injury and the comparability of the involved mechanisms between different sterile injuries are unknown. In this project we will perform a deep characterization of the systemic inflammatory response in experimental models of IS and MI and human patient material to identify specific key pathways as causative and druggable targets involved in plaque destabilization after remote injuries.

B12: Role of micronuclei-contained DNA and the cytosolic DNA sensor cGAS in atherosclerosis

Arterial predisposition to atherosclerosis is dictated by hemodynamic forces characterizing selective arterial sites and by epigenetic variations in endothelial cells (ECs). Epigenetic variations, like mutations and DNA damage, can promote the development of atherosclerosis and accumulate in cytosolic extracellular chromatin bodies termed micronuclei (MN). As the generation and role of endothelial MN in arterial susceptibility to atherosclerosis and atheroprogression is unknown, will first determine the cell cycle phase at which physiologic and pathologic micronuclei are generated in human aortic endothelial cells (HAoECs) and in mouse aorta (Aim 1), the DNA and de novo RNA synthesis content in MN by whole genome and RNA sequencing, and their role by delivering the genetic content in HAoECs as well as in ECs lining arterial mice vessels (Aim2). Finally, the role of cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) against MN and atherosclerosis will be tested by gain- and loss-of function studies in HAoECs as well as using ApoE-cGAS-double knockout mice (Aim 3).