Biology subjects

Marleau, S.

Publications and source records attributed to Marleau, S..

3 recordsLinked to original sources

bioRxiv2025

Cyclic azapeptide cluster of differentiation-36 receptor modulator attenuates left ventricular injury and temporarily reduces long-chain fatty acid accumulation after myocardial ischemia-reperfusion in mice

Ischemic heart disease remains a leading global cause of death. We investigated the cardio-protective effects of the selective cluster of differentiation-36 receptor (CD36) modulator azapeptide MPE-298 in a mouse model of myocardial ischemia-reperfusion. Before reperfusion, a single intravenous dose of azapeptide MPE-298 reduced infarct size by 37% and transiently decreased left ventricular (LV) long-chain fatty acid (LCFA) accumulation, independently of saturation status. Metabolomic profiling revealed shifts in amino acids involved in energy production and antioxidant defense. Gene expression analysis showed transient modulation of oxidative stress and inflammation in both heart and adipose tissue. Modulation of CD36 by azapeptide MPE-298 exhibited therapeutic potential for treating acute myocardial ischemia and reperfusion by supporting metabolic recovery and limiting excess LCFA uptake. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/674351v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11aa899org.highwire.dtl.DTLVardef@132fc5borg.highwire.dtl.DTLVardef@55c32forg.highwire.dtl.DTLVardef@81585f_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Early IKKb-dependent anabolic signature governs vascular smooth muscle cells fate and abdominal aortic aneurysm development

BackgroundAbdominal aortic aneurysm (AAA) is a detrimental disease with no effective pharmacological therapy. While inflammation is recognized as one of the key regulators of AAA, targeting inflammatory pathways once the disease is established does not impact the outcomes. However, understanding the earliest molecular indicators could shed light on the precise biological targets and prognostic markers for AAA. MethodsUsing apolipoprotein E (ApoE)-deficient mice fed with a standard diet and infused with Angiotensin II (Ang II), we conducted bulk RNA-sequencing (RNA-Seq) analysis on suprarenal (SRA) regions obtained from both unchallenged and challenged WT mice, specifically examining responses 24 hours after Ang II infusion to capture the initial phases of aortic stress response. We further created a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKK{beta}) can be conditionally (via tamoxifen injection) suppressed in vascular smooth muscle cells (VSMC). The development of AAA was evaluated using in situ examination and quantified using RT-qPCR, immunohistochemistry and fluorescence microscopy. Cultured VSMC were exposed to the selective IKK{beta} inhibitor MLN120b and the expression levels of phenotypic markers kruppel like factor 4 (KLF4), {beta}-Catenin and cellular communication network factor 2 (CCN2) were addressed using cellular extracts and immunoblot analysis. ResultsRNA-Seq data support the presence of early anabolic events in SRA regions detailing activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, which paralleled cellular anabolic processes including mitochondria, ribosome and sterol biosynthesis, the Unfolded Protein Response (UPR) and fibrogenesis. Conditional deletion of the Ikbkb gene in VSMC significantly reduces the incidence of SRA lesions as well as the rate of aneurysm ruptures in mice exposed to Ang II. In situ analysis further demonstrated that the protection conferred by the lack of IKK{beta} expression in VSMC is associated with reduced inflammatory response, the preservation of the contractile over the degradative VSMC phenotypes, and the absence of an anabolic signature. ConclusionOur results not only reinforce the major roles played by VSMC in the rapid adaptation leading to the deleterious remodeling of the vascular wall and aortic lesions but also support a paradigm aiming at repositioning the efforts focusing on anabolic rather than inflammatory events.

molecular biology↗

bioRxiv2023

Novel chP3R99 mAb reduces subendothelial retention of atherogenic lipoproteins in Insulin-Resistant rats: Acute treatment versus long-term protection as an idiotypic vaccine for atherosclerosis

BACKGROUNDAtherosclerosis is triggered by the retention of apolipoprotein B-containing lipoproteins by proteoglycans. In addition to LDL, remnant lipoproteins have emerged as pivotal contributors to this pathology, particularly in the context of insulin resistance and diabetes. We have previously reported anti-atherogenic properties of a monoclonal antibody (chP3R99) that recognizes sulfated glycosaminoglycans on arterial proteoglycans. METHODS AND RESULTSSolid-phase assays demonstrated that chP3R99 effectively blocked over 50% lipoprotein binding to chondroitin sulfate and vascular extracellular matrix in vitro. The pre-perfusion of chP3R99 (competitive effect) resulted in specific antibody-arterial accumulation and reduced fluorescent lipoprotein retention by [~]60% in insulin resistant JCR:LA-cp rats. This competitive reduction was dose-dependent (25 {micro}g/mL-250 {micro}g/mL), effectively decreasing deposition of cholesterol associated with lipoproteins. In a five-week vaccination study in insulin resistant rats with (200 {micro}g SC, once a week), chP3R99 reduced arterial lipoprotein retention, and was associated with the production of anti-chondroitin sulfate antibodies (Ab3) able to accumulate in the arteries (dot-blot). Neither the intravenous inoculation of chP3R99 (4.5 mg/kg), nor the immunization with this antibody displayed adverse effects on lipid or glucose metabolism, insulin resistance, liver function, blood cell indices, or inflammation pathways in JCR:LA-cp rats. CONCLUSIONSBoth acute (passive) and long-term administration (idiotypic cascade) of chP3R99 antibody reduced LDL and remnant lipoprotein interaction with proteoglycans in an insulin-resistant setting. These findings support the innovative approach of targeting pro-atherogenic lipoprotein retention by chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis. CLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSO_LIInnovative anti-atherosclerotic chP3R99 mAb interferes with proteoglycan binding of both LDL and remnant lipoproteins in vitro and in vivo. C_LIO_LIIn vivo kinetic studies that immunize with chP3R99 reveal a temporal induction of an anti-idiotypic antibody cascade in a model of insulin resistance (analogous to a vaccine). C_LIO_LIWe discovered that the idiotypic chP3R99 monoclonal antibody (Ab1) was able to induce protective anti-anti-idiotypic (Ab3) antibodies present in both sera as well as the aorta (target organ) in vivo. C_LI What Are The Clinical Implications?O_LIThe chP3R99 mAb has efficacy for reducing the arterial retention of both LDL and remnant-derived lipoproteins and may be relevant of those with Type-2 Diabetes and/or residual CVD risk. C_LIO_LIWe show efficacy of chP3R99 mAb under pro-inflammatory conditions and that it does not exacerbate other metabolic aberrations during insulin resistance. C_LIO_LIData support the targeting pro-atherogenic lipoprotein retention with chP3R99 as a passive therapy or as an idiotypic vaccine for atherosclerosis, complementary to lipid lowering approaches. C_LI

pathology↗