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Objective— Recently, poliovirus receptor–related 2 ( Pvrl2 ) emerged as a top gene in a global gene expression study aiming to detect plasma cholesterol–responsive genes causally related to atherosclerosis regression in hypercholesterolemic mice. PVRL2 is an adherens junction protein implied to play a role in transendothelial migration of leukocytes, a key feature in atherosclerosis development. In this study, we investigated the effect of Pvrl2 deficiency on atherosclerosis development and transendothelial migration of leukocytes activity. Approach and Results— Pvrl2 -deficient mice bred onto an atherosclerosis-prone background ( Pvrl2 −/− Ldlr −/− Apob 100/100 ) had less atherosclerotic lesions and more stable plaques compared with littermate controls ( Pvrl2 +/+ Ldlr −/− Apob 100/100 ). Pvrl2 −/− Ldlr −/− Apob 100/100 mice also showed a 49% decrease in transendothelial migration of leukocytes activity observed using the in vivo air pouch model. In accordance, augmented arterial wall expression of Pvrl2 during atherosclerosis progression coincided with an increased gene expression of migrating leukocytes into the vessel wall. Both in human and mice, gene and protein expression of PVRL2 was predominantly observed in the vascular endothelium according to the immunohistochemical and gene expression data. In addition, the cholesterol responsiveness of PVRL2 was also observed in humans. Conclusions— PVRL2 is a plasma cholesterol–responsive gene acting at endothelial sites of vascular inflammation that could potentially be a new therapeutic target for atherosclerosis prevention through its suggested transendothelial migration of leukocytes modulating activity.

Background: Antiretroviral therapy (ART) for HIV infection increases risk for coronary artery disease (CAD), presumably by causing dyslipidemia and increased atherosclerosis. We applied systems pharmacology to identify and validate specific regulatory gene networks through which ART drugs may promote CAD. Methods: Transcriptional responses of human cell lines to 15 ART drugs retrieved from the Library of Integrated Cellular Signatures (overall 1127 experiments) were used to establish consensus ART gene/transcriptional signatures. Next, enrichments of differentially expressed genes and gene-gene connectivity within these ART-consensus signatures were sought in 30 regulatory gene networks associated with CAD and CAD-related phenotypes in the Stockholm Atherosclerosis Gene Expression study. Results: Ten of 15 ART signatures were significantly enriched both for differential expression and connectivity in a specific atherosclerotic arterial wall regulatory gene network (AR-RGN) causal for CAD involving RNA processing genes. An atherosclerosis in vitro model of cholestryl ester-loaded foam cells was then used for experimental validation. Treatments of these foam cells with ritonavir, nelfinavir, and saquinavir at least doubled cholestryl ester accumulation ( P =0.02, 0.0009, and 0.02, respectively), whereas RNA silencing of the AR-RGN top key driver, PQBP1 (polyglutamine binding protein 1), significantly curbed cholestryl ester accumulation following treatment with any of these ART drugs by >37% ( P Conclusions: By applying a novel systems pharmacology data analysis framework, 3 commonly used ARTs (ritonavir, nelfinavir, and saquinavir) were found altering the activity of AR-RGN, a regulatory gene network promoting foam cell formation and risk of CAD. Targeting AR-RGN or its top key driver PQBP1 may help reduce CAD side effects of these ART drugs.

Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks (“modules”). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene–protein interactions directly affected by genetic variance in CAD risk loci.

Background and aims Mitochondrial damage and augmented production of reactive oxygen species (ROS) may represent an intermediate step by which hypercholesterolemia exacerbates atherosclerotic lesion formation. Methods To test this hypothesis, in mice with severe but genetically reversible hypercholesterolemia (i.e. the so called Reversa mouse model), we performed time-resolved analyses of mitochondrial transcriptome in the aortic arch employing a systems-level network approach. Results During hypercholesterolemia, we observed a massive down-regulation (>28%) of mitochondrial genes, specifically at the time of rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age. Both phenomena - down-regulation of mitochondrial genes and lesion expansion - were largely reversible by genetically lowering plasma cholesterol (by >80%, from 427 to 54 ± 31 mg/L) at 30 weeks. Co-expression network analysis revealed that both mitochondrial signature genes were highly connected in two modules, negatively correlating with lesion size and supported as causal for coronary artery disease (CAD) in humans, as expression-associated single nucleotide polymorphisms (eSNPs) representing their genes overlapped markedly with established disease risk loci. Within these modules, we identified the transcription factor estrogen related receptor (ERR)-α and its co-factors PGC1-α and -β, i.e. two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators, as key regulatory genes. Together, these factors are known as major orchestrators of mitochondrial biogenesis and antioxidant responses. Conclusions Using a network approach, we demonstrate how hypercholesterolemia could hamper mitochondrial activity during atherosclerosis progression and pinpoint potential therapeutic targets to counteract these processes.