ANGPTL2 promotes immune checkpoint inhibitor-related murine autoimmune myocarditis

Abstract Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy advances rapidly in the clinic. Despite their therapeutic benefits, ICIs can cause clinically significant immune-related adverse events (irAEs), including myocarditis. However, the cellular and molecular mechanisms regulating irAE remain unclear. Here, we investigate the function of Angiopoietin-like protein 2 (ANGPTL2), a potential inflammatory mediator, in a mouse model of ICI-related autoimmune myocarditis. ANGPTL2 deficiency attenuates autoimmune inflammation in these mice, an outcome associated with decreased numbers of T cells and macrophages. We also show that cardiac fibroblasts express abundant ANGPTL2. Importantly, cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues. Our findings suggest an immunostimulatory function for ANGPTL2 in the context of ICI-related autoimmune inflammation and highlight the pathophysiological significance of ANGPTL2-mediated cardiac myofibroblast/immune cell crosstalk in enhancing autoimmune responses. These findings overall provide insight into mechanisms regulating irAEs

Aging- and obesity-related peri-muscular adipose tissue accelerates muscle atrophy.

Sarcopenia due to loss of skeletal muscle mass and strength leads to physical inactivity and decreased quality of life. The number of individuals with sarcopenia is rapidly increasing as the number of older people increases worldwide, making this condition a medical and social problem. Some patients with sarcopenia exhibit accumulation of peri-muscular adipose tissue (PMAT) as ectopic fat deposition surrounding atrophied muscle. However, an association of PMAT with muscle atrophy has not been demonstrated. Here, we show that PMAT is associated with muscle atrophy in aged mice and that atrophy severity increases in parallel with cumulative doses of PMAT. We observed severe muscle atrophy in two different obese model mice harboring significant PMAT relative to respective control non-obese mice. We also report that denervation-induced muscle atrophy was accelerated in non-obese young mice transplanted around skeletal muscle with obese adipose tissue relative to controls transplanted with non-obese adipose tissue. Notably, transplantation of obese adipose tissue into peri-muscular regions increased nuclear translocation of FoxO transcription factors and upregulated expression FoxO targets associated with proteolysis (Atrogin1 and MuRF1) and cellular senescence (p19 and p21) in muscle. Conversely, in obese mice, PMAT removal attenuated denervation-induced muscle atrophy and suppressed upregulation of genes related to proteolysis and cellular senescence in muscle. We conclude that PMAT accumulation accelerates age- and obesity-induced muscle atrophy by increasing proteolysis and cellular senescence in muscle

Efficacy and safety in mice of repeated, lifelong administration of an ANGPTL3 vaccine

Abstract Previously, we reported that an ANGPTL3 vaccine is a hopeful therapeutic option against dyslipidemia. In our current study, we assess durability and booster effects of that vaccine over a period representing a mouse’s lifespan. The vaccine remained effective for over one year, and booster vaccination maintained suppression of circulating triglyceride levels thereafter without major adverse effects on lungs, kidneys, or liver, suggesting vaccine efficacy and safety

ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure

Cdk5rap1-Mediated 2-Methylthio Modification of Mitochondrial tRNAs Governs Protein Translation and Contributes to Myopathy in Mice and Humans

SummaryTransfer RNAs (tRNAs) contain a wide variety of posttranscriptional modifications that are important for accurate decoding. Mammalian mitochondrial tRNAs (mt-tRNAs) are modified by nuclear-encoded tRNA-modifying enzymes; however, the physiological roles of these modifications remain largely unknown. In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methylthio (ms2) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms2 modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress-induced mitochondrial remodeling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms2 modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms2 modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease

Association between circulating ANGPTL levels and general medical status (n = 800).

<p>A generalized linear model was used. All variables listed were included in the model. ANGPTL, Angiopoietin-like protein; β, regression coefficient; 95% CI, 95% confidence interval; P, probability; and CKD, chronic kidney disease.</p

Baseline characteristics of study population subjects.

<p>Data is shown as the median or interquartile range (IQR); BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA_1C, hemoglobin A_1C; LDL, low-density lipoprotein; HDL, high-density lipoprotein; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyltransferase; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; and hs-CRP, high-sensitivity C reactive protein.</p

Association between circulating ANGPTL3 levels and lab values relevant to hepatic impairment or inflammation (n = 800).

<p>A generalized linear model was used. To evaluate AST, ALT or GGT, covariates were adjusted by all variables listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193731#pone.0193731.t003" target="_blank">Table 3</a>, minus the hepatic impairment category. To evaluate hs-CRP, covariates were adjusted by all variables listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193731#pone.0193731.t003" target="_blank">Table 3</a>, minus the inflammation category. β, regression coefficient; 95% CI, 95% confidence interval; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyltransferase; and hs-CRP, high sensitivity C reactive protein.</p