Effect of Paxlovid in COVID-19 treatment during the periods of SARS-CoV-2 Omicron BA.5 and BN.1 subvariant dominance in the Republic of Korea: a retrospective cohort study.

BACKGROUND: This study was conducted to assess the efficacy of nirmatrelvir/ritonavir treatment in patients with coronavirus disease 2019 (COVID-19), particularly those aged 60 years and older. Using real-world data, the period during which the BN.1 Omicron variant was dominant was compared to the period dominated by the BA.5 variant. METHODS: In this retrospective cohort study, data were collected regarding 2,665,281 patients infected with severe acute respiratory syndrome coronavirus 2 between July 24, 2022, and March 31, 2023. Propensity score matching was utilized to match patients who received nirmatrelvir/ ritonavir in a 1:4 ratio between BN.1 and BA.5 variant groups. Multivariable logistic regression analysis was employed to assess the effects of nirmatrelvir/ritonavir within these groups. RESULTS: Compared to the prior period, the efficacy of nirmatrelvir/ritonavir did not significantly differ during the interval of Omicron BN.1 variant dominance in the Republic of Korea. Among patients treated with nirmatrelvir/ritonavir, a significantly lower risk of mortality was observed in the BN.1 group (odds ratio [OR], 0.698; 95% confidence interval [CI], 0.557-0.875) compared to the BA.5 group. However, this treatment did not significantly reduce the risk of severe or critical illness, including death, for those in the BN.1 group (OR, 0.856; 95% CI, 0.728-1.007). CONCLUSION: Nirmatrelvir/ritonavir has maintained its effectiveness against COVID-19, even with the emergence of the BN.1 Omicron subvariant. Consequently, we strongly recommend the administration of nirmatrelvir/ritonavir to patients exhibiting COVID-19-related symptoms, irrespective of the dominant Omicron variant or their vaccination status, to mitigate disease severity and decrease the risk of mortality.

Identification of a leucine-mediated threshold effect governing macrophage mTOR signalling and cardiovascular risk.

High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.

Risk factors for transmission in a COVID-19 cluster infection in a high school in the Republic of Korea.

BACKGROUND: This study aimed to examine the scale, characteristics, risk factors, and modes of transmission in a coronavirus disease 2019 (COVID-19) outbreak at a high school in Seoul, Republic of Korea. METHODS: An epidemiological survey was conducted of 1,118 confirmed cases and close contacts from a COVID-19 outbreak at an educational facility starting on May 31, 2021. In-depth interviews, online questionnaires, flow evaluations, and CCTV analyses were used to devise infection prevention measures. Behavioral and spatial risk factors were identified, and statistical significance was tested. RESULTS: Among 3rd-year students, there were 33 confirmed COVID-19 cases (9.6%). Students who used a study room in the annex building showed a statistically significant 4.3-fold elevation in their relative risk for infection compared to those who did not use the study room. Moreover, CCTV facial recognition analysis confirmed that 17.8% of 3rd-year students did not wear masks and had the lowest percentage of mask-wearers by grade. The air epidemiological survey conducted in the study room in the annex, which met the 3 criteria for a closed space, confirmed that there was only 10% natural ventilation due to the poor ventilation system. CONCLUSION: To prevent and manage the spread of COVID-19 in educational facilities, advance measures that consider the size, operation, and resources of each school are crucial. In addition, various survey methodologies should be used in future studies to quickly analyze a wider range of data that can inform an evidence-based quarantine response.

Unbalanced Redox With Autophagy in Cardiovascular Disease.

Precise redox balance is essential for the optimum health and physiological function of the human body. Furthermore, an unbalanced redox state is widely believed to be part of numerous diseases, ultimately resulting in death. In this review, we discuss the relationship between redox balance and cardiovascular disease (CVD). In various animal models, excessive oxidative stress has been associated with increased atherosclerotic plaque formation, which is linked to the inflammation status of several cell types. However, various antioxidants can defend against reactive oxidative stress, which is associated with an increased risk of CVD and mortality. The different cardiovascular effects of these antioxidants are presumably due to alterations in the multiple pathways that have been mechanistically linked to accelerated atherosclerotic plaque formation, macrophage activation, and endothelial dysfunction in animal models of CVD, as well as in in vitro cell culture systems. Autophagy is a regulated cell survival mechanism that removes dysfunctional or damaged cellular organelles and recycles the nutrients for the generation of energy. Furthermore, in response to atherogenic stress, such as the generation of reactive oxygen species, oxidized lipids, and inflammatory signaling between cells, autophagy protects against plaque formation. In this review, we characterize the broad spectrum of oxidative stress that influences CVD, summarize the role of autophagy in the content of redox balance-associated pathways in atherosclerosis, and discuss potential therapeutic approaches to target CVD by stimulating autophagy.

Loss of Macrophage mTORC2 Drives Atherosclerosis via FoxO1 and IL-1ß Signaling.

BACKGROUND: The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages. METHODS: Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. RESULTS: In contrast to the atheroprotective effect seen with blockade of macrophage mTORC1, macrophage-specific mTORC2-deficient mice exhibit an atherogenic phenotype, with larger, more complex lesions and increased cell death. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 (forkhead box protein O1) transcription factor, leading to suppression of proinflammatory pathways, especially the inflammasome/IL (interleukin)-1ß response, a key mediator of vascular inflammation and atherosclerosis. In addition, administration of FoxO1 inhibitors efficiently rescued the proinflammatory response caused by mTORC2 deficiency both in vitro and in vivo. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these signaling arms. CONCLUSIONS: Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.

Subcutaneous Transplantation of White Adipose Tissue.

In the research setting, white adipose tissue (WAT) transplantation, also known as fat transplantation, is often used to understand the physiological function of adipocytes or associated stromal vascular cells such as macrophages in the context of local and systemic metabolism. The mouse is the most common animal model used where WAT from a donor is transferred either to a subcutaneous site of the same organism or to a subcutaneous region of a recipient. Here, we describe in detail the procedure for heterologous fat transplantation, and, given the need for survival surgery, peri- and postoperative care and subsequent histological confirmation of fat grafts will also be discussed.

Use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in atherosclerosis.

Dysfunction in the macrophage lysosomal system including reduced acidity and diminished degradative capacity is a hallmark of atherosclerosis, leading to blunted clearance of excess cellular debris and lipids in plaques and contributing to lesion progression. Devising strategies to rescue this macrophage lysosomal dysfunction is a novel therapeutic measure. Nanoparticles have emerged as an effective platform to both target specific tissues and serve as drug delivery vehicles. In most cases, administered nanoparticles are taken up non-selectively by the mononuclear phagocyte system including monocytes/macrophages leading to the undesirable degradation of cargo in lysosomes. We took advantage of this default route to target macrophage lysosomes to rectify their acidity in disease states such as atherosclerosis. Herein, we develop and test two commonly used acidic nanoparticles, poly-lactide-co-glycolic acid (PLGA) and polylactic acid (PLA), both in vitro and in vivo. Our results in cultured macrophages indicate that the PLGA-based nanoparticles are the most effective at trafficking to and enhancing acidification of lysosomes. PLGA nanoparticles also provide functional benefits including enhanced lysosomal degradation, promotion of macroautophagy/autophagy and protein aggregate removal, and reduced apoptosis and inflammasome activation. We demonstrate the utility of this system in vivo, showing nanoparticle accumulation in, and lysosomal acidification of, macrophages in atherosclerotic plaques. Long-term administration of PLGA nanoparticles results in significant reductions in surrogates of plaque complexity with reduced apoptosis, necrotic core formation, and cytotoxic protein aggregates and increased fibrous cap formation. Taken together, our data support the use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in the treatment of atherosclerosis.Abbreviations: BCA: brachiocephalic arteries; FACS: fluorescence activated cell sorting; FITC: fluorescein-5-isothiocyanatel; IL1B: interleukin 1 beta; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; LSDs: lysosomal storage disorders; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MPS: mononuclear phagocyte system; PEGHDE: polyethylene glycol hexadecyl ether; PLA: polylactic acid; PLGA: poly-lactide-co-glycolic acid; SQSTM1/p62: sequestosome 1.

Systemic Lupus Erythematosus and Lung Involvement: A Comprehensive Review.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan manifestations, including pleuropulmonary involvement (20-90%). The precise mechanism of pleuropulmonary involvement in SLE is not well-understood; however, systemic type 1 interferons, circulating immune complexes, and neutrophils seem to play essential roles. There are eight types of pleuropulmonary involvement: lupus pleuritis, pleural effusion, acute lupus pneumonitis, shrinking lung syndrome, interstitial lung disease, diffuse alveolar hemorrhage (DAH), pulmonary arterial hypertension, and pulmonary embolism. DAH has a high mortality rate (68-75%). The diagnostic tools for pleuropulmonary involvement in SLE include chest X-ray (CXR), computed tomography (CT), pulmonary function tests (PFT), bronchoalveolar lavage, biopsy, technetium-99m hexamethylprophylene amine oxime perfusion scan, and (18)F-fluorodeoxyglucose positron emission tomography. An approach for detecting pleuropulmonary involvement in SLE includes high-resolution CT, CXR, and PFT. Little is known about specific therapies for pleuropulmonary involvement in SLE. However, immunosuppressive therapies such as corticosteroids and cyclophosphamide are generally used. Rituximab has also been successfully used in three of the eight pleuropulmonary involvement forms: lupus pleuritis, acute lupus pneumonitis, and shrinking lung syndrome. Pleuropulmonary manifestations are part of the clinical criteria for SLE diagnosis. However, no review article has focused on the involvement of pleuropulmonary disease in SLE. Therefore, this article summarizes the literature on the epidemiology, pathogenesis, diagnosis, and management of pleuropulmonary involvement in SLE.

Evaluation of mTORC1 signaling in mouse atherosclerotic macrophages by flow cytometry and immunofluorescence.

Previous studies have demonstrated that a high-protein diet leads to increased atherosclerosis in mice, and that this adverse effect is caused by activation of macrophage mTORC1 signaling. Here, we provide a detailed protocol for the evaluation of diet-induced mTORC1 signaling in plaque macrophages in atherosclerosis-prone apolipoprotein E (ApoE) knockout (KO) mice. This protocol includes flow cytometry and immunofluorescence analysis of atherosclerotic macrophages that can be used to study the atherogenic potential of a variety of mTORC1 modulators. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2020).

Plasma Membrane Localization of CD36 Requires Vimentin Phosphorylation; A Mechanism by Which Macrophage Vimentin Promotes Atherosclerosis.

Vimentin is a type III intermediate filament protein expressed in cells of mesenchymal origin. Vimentin has been thought to function mainly as a structural protein and roles of vimentin in other cellular processes have not been extensively studied. Our current study aims to reveal functions of vimentin in macrophage foam cell formation, the critical stage of atherosclerosis. We demonstrated that vimentin null (Vim -/ - ) mouse peritoneal macrophages take up less oxidized LDL (oxLDL) than vimentin wild type (Vim +/+) macrophages. Despite less uptake of oxLDL in Vim -/ - macrophages, Vim +/+ and Vim -/ - macrophages did not show difference in expression of CD36 known to mediate oxLDL uptake. However, CD36 localized in plasma membrane was 50% less in Vim -/ - macrophages than in Vim +/+ macrophages. OxLDL/CD36 interaction induced protein kinase A (PKA)-mediated vimentin (Ser72) phosphorylation. Cd36 -/ - macrophages did not exhibit vimentin phosphorylation (Ser72) in response to oxLDL. Experiments using phospho-mimetic mutation of vimentin revealed that macrophages with aspartate-substituted vimentin (V72D) showed more oxLDL uptake and membrane CD36. LDL receptor null (Ldlr -/ - ) mice reconstituted with Vim -/ - bone marrow fed a western diet for 15 weeks showed 43% less atherosclerotic lesion formation than Ldlr -/ - mice with Vim +/+ bone marrow. In addition, Apoe -/ -Vim- / - (double null) mice fed a western diet for 15 weeks also showed 57% less atherosclerotic lesion formation than Apoe -/ - and Vim +/+mice. We concluded that oxLDL via CD36 induces PKA-mediated phosphorylation of vimentin (Ser72) and phosphorylated vimentin (Ser72) directs CD36 trafficking to plasma membrane in macrophages. This study reveals a function of vimentin in CD36 trafficking and macrophage foam cell formation and may guide to establish a new strategy for the treatment of atherosclerosis.

The antioxidant enzyme Peroxiredoxin-1 controls stroke-associated microglia against acute ischemic stroke.

Ischemic stroke is the leading cause of immortal disability and death worldwide. For treatment in the acute phase, it is necessary to control excessive reactive oxygen species (ROS) damage during ischemia/reperfusion (I/R). Microglia are well known to be closely associated with excessive ROS response in the early stage of I/R. However, the precise roles of microglia associated with mitigating ROS damage, and molecular markers of heterogenetic microglia in the I/R damaged brain has not been clarified. Here, we identified a new type of microglia associated with stroke in the I/R injured brain. Single-cell RNA sequencing (scRNA-seq) was used to assess transcriptional changes of microglia and immune cells in the contralateral (CL) and ipsilateral (IL) hemispheres after transient middle cerebral artery occlusion (tMCAO) surgery to mimic ischemic stroke. We classified a unique type of microglia with enhanced antioxidant function and markers similar to those of disease-associated microglia (DAM), designated them as stroke-associated microglia (SAM). The representative antioxidant enzyme, Peroxiredoxin-1 (Prdx1), was predominantly expressed in SAM and mediated ROS defense genes, including Txn1, Srx1, Mt1, and Mt2. In the Prdx1-/- I/R damaged brain, we observed significantly increased infarction, as assessed by TTC staining, and FACS analysis detected severe microglial cell death. Importantly, scRNA transcriptomics data showed that the SAM population was specifically decreased in Prdx1-/- mice and that these mice exhibited decreased ROS damage resistance. Inflammatory responses which were detected by ELISA and qPCR, were also increased in Prdx1-/- IL hemispheres. Finally, Prdx1-dependent antioxidative SAM were found to be essential for increasing the transcription levels of stroke-protective molecules, such as osteopontin and ferritin. A novel microglia type (SAM) is specifically activated in response to stroke I/R injury, and that Prdx1 expression is required for the activation and enhanced antioxidant function of SAM.

TFEB signaling attenuates NLRP3-driven inflammatory responses in severe asthma.

BACKGROUND: NLRP3-driven inflammatory responses by circulating and lung-resident monocytes are critical drivers of asthma pathogenesis. Autophagy restrains NLRP3-induced monocyte activation in asthma models. Yet, the effects of autophagy and its master regulator, transcription factor EB (TFEB), on monocyte responses in human asthma remain unexplored. Here, we investigated whether activation of autophagy and TFEB signaling suppress inflammatory monocyte responses in asthmatic individuals. METHODS: Peripheral blood CD14+ monocytes from asthmatic patients (n = 83) and healthy controls (n = 46) were stimulated with LPS/ATP to induce NLRP3 activation with or without the autophagy inducer, rapamycin. ASC specks, caspase-1 activation, IL-1ß and IL-18 levels, mitochondrial function, ROS release, and mTORC1 signaling were examined. Autophagy was evaluated by LC3 puncta formation, p62/SQSTM1 degradation and TFEB activation. In a severe asthma (SA) model, we investigated the role of NLRP3 signaling using Nlrp3-/- mice and/or MCC950 administration, and the effects of TFEB activation using myeloid-specific TFEB-overexpressing mice or administration of the TFEB activator, trehalose. RESULTS: We observed increased NLRP3 inflammasome activation, concomitant with impaired autophagy in circulating monocytes that correlated with asthma severity. SA patients also exhibited mitochondrial dysfunction and ROS accumulation. Autophagy failed to inhibit NLRP3-driven monocyte responses, due to defective TFEB activation and excessive mTORC1 signaling. NLRP3 blockade restrained inflammatory cytokine release and linked airway disease. TFEB activation restored impaired autophagy, attenuated NLRP3-driven pulmonary inflammation, and ameliorated SA phenotype. CONCLUSIONS: Our studies uncover a crucial role for TFEB-mediated reprogramming of monocyte inflammatory responses, raising the prospect that this pathway can be therapeutically harnessed for the management of SA.

A role of anterior cingulate cortex in the emergence of worker-parasite relationship.

We studied the brain mechanisms underlying action selection in a social dilemma setting in which individuals' effortful gains are unfairly distributed among group members. A stable "worker-parasite" relationship developed when three individually operant-conditioned rats were placed together in a Skinner box equipped with response lever and food dispenser on opposite sides. Specifically, one rat, the "worker," engaged in lever-pressing while the other two "parasitic" rats profited from the worker's effort by crowding the feeder in anticipation of food. Anatomically, c-Fos expression in the anterior cingulate cortex (ACC) was significantly higher in worker rats than in parasite rats. Functionally, ACC inactivation suppressed the worker's lever-press behavior drastically under social, but only mildly under individual, settings. Transcriptionally, GABAA receptor- and potassium channel-related messenger RNA expressions were reliably lower in the worker's, relative to parasite's, ACC. These findings indicate the requirement of ACC activation for the expression of exploitable, effortful behavior, which could be mediated by molecular pathways involving GABAA receptor/potassium channel proteins.

Naa12 compensates for Naa10 in mice in the amino-terminal acetylation pathway.

Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking Naa10 show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather Naa10 nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies. Naa12 is a previously unannotated Naa10-like paralog with NAT activity that genetically compensates for Naa10. Mice deficient for Naa12 have no apparent phenotype, whereas mice deficient for Naa10 and Naa12 display embryonic lethality. The discovery of Naa12 adds to the currently known machinery involved in amino-terminal acetylation in mice.

Peroxiredoxins as Potential Targets for Cardiovascular Disease.

Increased oxidative stress (OS) is considered a common etiology in the pathogenesis of cardiovascular disease (CVD). Therefore, the precise regulation of reactive oxygen species (ROS) in cardiovascular cells is essential to maintain normal physiological functions. Numerous regulators of cellular homeostasis are reportedly influenced by ROS. Hydrogen peroxide (H2O2), as an endogenous ROS in aerobic cells, is a toxic substance that can induce OS. However, many studies conducted over the past two decades have provided substantial evidence that H2O2 acts as a diffusible intracellular signaling messenger. Antioxidant enzymes, including superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins (Prdxs), maintain the balance of ROS levels against augmentation of ROS production during the pathogenesis of CVD. Especially, Prdxs are regulatory sensors of transduced intracellular signals. The intracellular abundance of Prdxs that specifically react with H2O2 act as regulatory proteins. In this review, we focus on the role of Prdxs in the regulation of ROS-induced pathological changes in the development of CVD.

Social isolation impairs the prefrontal-nucleus accumbens circuit subserving social recognition in mice.

Although medial prefrontal cortex (mPFC) is known to play important roles in social behaviors, how early social experiences affect the mPFC and its subcortical circuit remains unclear. We report that mice singly housed (SH) for 8 weeks after weaning show a social recognition deficit, even after 4 weeks of resocialization. In SH mice, prefrontal infralimbic (IL) neurons projecting to the shell region of nucleus accumbens (NAcSh) show decreased excitability compared with group-housed (GH) mice. NAcSh-projecting IL neurons are activated when GH mice encounter a familiar conspecific, which is not observed in SH mice. Chemogenetic inhibition of NAcSh-projecting IL neurons in normal mice impairs social recognition without affecting social preference, whereas activation of these neurons reverses social recognition deficit in SH mice. Our findings demonstrate that early social experience critically affects mPFC IL-NAcSh projection, the activation of which is required for social recognition by encoding information for social familiarity.

Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response.

The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system.Abbreviations: ASO: antisense oligonucleotide; AU: arbitrary units; BMDM: bone marrow-derived macrophages; CLFs: crude lysosomal fractions; CTSD: cathepsin D; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; MAP1LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; pMAC: peritoneal macrophages; SLC2A8/GLUT8: solute carrier family 2, (facilitated glucose transporter), member 8; TFEB: transcription factor EB; TMR: tetramethylrhodamine; TREH: trehalase.

Deficiency of peroxiredoxin 2 exacerbates angiotensin II-induced abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease characterized by structural deterioration of the aorta caused by inflammation and oxidative stress, leading to aortic dilatation and rupture. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, has been reported as a potential negative regulator of inflammatory vascular diseases, and it has been identified as a protein that is increased in patients with ruptured AAA compared to patients with nonruptured AAA. In this study, we demonstrated that PRDX2 was a pivotal factor involved in the inhibition of AAA progression. PRDX2 levels were increased in AAA compared with those in normal aortas in both humans and mice. Ultrasound imaging revealed that the loss of PRDX2 accelerated the development of AAA in the early stages and increased AAA incidence in mice infused with angiotensin II (Ang II). Prdx2-/- mice infused with Ang II exhibited increased aortic dilatation and maximal aortic diameter without a change in blood pressure. Structural deterioration of the aortas from Prdx2-/- mice infused with Ang II was associated with increases in the degradation of elastin, oxidative stress, and intramural thrombi caused by microhemorrhages, immature neovessels, and the activation of matrix metalloproteinases compared to that observed in controls. Moreover, an increase in inflammatory responses, including the production of cell adhesion molecules and the accumulation of inflammatory cells and proinflammatory cytokines due to PRDX2 deficiency, accelerated Ang II-induced AAA progression. Our data confirm that PRDX2 plays a role as a negative regulator of the pathological process of AAA and suggest that increasing PRDX2 activity may be a novel strategy for the prevention and treatment of AAA.

Author Correction: High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.