Biology subjects

Delafontaine, P.

Publications and source records attributed to Delafontaine, P..

5 recordsLinked to original sources

bioRxiv2025

LARP6 Promotes Features of Plaque Stability and Smooth Muscle Cell Survival in Atherosclerosis

IntroductionAcute plaque rupture or erosion followed by luminal thrombosis is a major cause of myocardial infarction and sudden cardiac death. Vulnerable plaques are characterized by a thin fibrous cap and reduced numbers of smooth muscle cells (SMCs). SMCs are essential for plaque stability, as they synthesize collagen and support fibrous cap structure. Our previous work demonstrated that insulin-like growth factor-1(IGF-1) enhances plaque stability and upregulates La ribonucleoprotein domain family member 6 (Larp6), a collagen mRNA-binding protein in SMCs. However, the specific role of Larp6 in atherosclerotic plaque stability remains undefined. MethodsIn vitro, human aortic SMCs (hAoSMCs) were used to investigate the molecular mechanism underlying IGF-1 regulation of LARP6. Using the Myh11 promotor we generated SMC specific Larp6 overexpression mice on an ApoE-/- background (SMC-Larp6) to assess effects on plaque stability. Bulk RNA sequencing data from human atherosclerotic plaques (GSE120521) were analyzed to compare stable and vulnerable plaques. ResultsIGF-1 regulates LARP6 through phosphorylation and downregulation of microRNAs. Plaques from SMC-Larp6 mice exhibited a significantly higher collagen content, accompanied by a thicker fibrous cap and a smaller necrotic core, increased presence of SMCs, without changes in overall plaque burden compared to controls. LARP6 overexpression in hAoSMCs significantly increased cell proliferation and survival under oxidative stress and promoted collagen accumulation by enhancing collagen synthesis. RNA sequencing analysis of human atherosclerotic plaques revealed reduced expression of LARP6 and downregulation of extracellular matrix-related pathways in unstable plaques, underscoring the clinical relevance of these findings. ConclusionsLarp6 overexpression promotes SMC survival, collagen synthesis and features of plaque stability under atherosclerotic conditions. These findings suggest that Larp6 is a potential therapeutic target for stabilization of atherosclerotic plaques.

pathology↗

bioRxiv2025

Persistent Activation of Monocytes/Macrophages and Cell Senescence in SIV-Infected Macaques on ART

Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-{kappa}B signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-{kappa}B, and inflammasome (NLRP3/or NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-{kappa}B activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART- treated macaque revealed macrophage-rich plaques with p21 senescent cells with intraluminal thrombus formation, recapitulating key features of HIV-associated atherogenesis. Together, these findings demonstrate that while ART normalizes acute infection-induced immune dysregulation, chronic SIV infection sustains a chronic, macrophage- and TLR-driven inflammatory state linked to vascular injury and aging process regardless of long-term suppression of viremia. Targeting inflammasome, NF-{kappa}B, and senescence pathways may mitigate non-AIDS comorbidities in PLWH.

immunology↗

bioRxiv2025

Coronary atherosclerotic plaque composition and classification in hypercholesterimic pigs

Rapacz pigs with familial hypercholesterolemia (FH pigs) fed with high-fat diet (HFD) develop early atherosclerotic lesions and complex atheromas in coronaries mimicking human coronary atherosclerotic disease (CAD). FH pigs have proven to be an excellent model for basic and pre-clinical atherosclerosis-focused research. However, unlike human atherosclerosis there has been no established classification system for porcine atherosclerosis. We isolated 104 plaque-containing coronary fragments from atherosclerotic FH pigs. A set of indices (features) of vessel and plaque morphology were quantified for each plaque, including intima-media ratio, vessel size, necrotic core area and fibrous cap thickness. Multifeatured clustering algorithm identified 4 clearly distinguishable plaque groups (A-D). Plaque cellular composition was assessed by immunohistochemistry to quantify relative level of smooth muscle-like, endothelial-like and macrophage-like cells. Plaque neovascularization, collagen levels, calcification and features of vulnerable plaque were assessed and used as additional numerical criteria for plaque classification and to establish the similarity of porcine plaque to specific types of human lesions. Our results indicate that porcine plaque type A, B, C and D correspond to human type III (intermediate lesion), type IV (atheroma), type V (fibroatheroma) and type VI (high-risk vulnerable plaque), respectively. Overall, our data demonstrates the suitability of using the FH pig as a pre-clinical model of human-like coronary atherosclerosis with great potential to advance emergent research in the field of CAD, especially in study of vulnerable plaque and in discovery research.

pathology↗

bioRxiv2022

Angiotensin II Type 2 Receptor Potentiates Skeletal Muscle Satellite Cell Differentiation via the GSK3β/β-catenin Pathway

Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased systemic angiotensin II (Ang II) levels and cachexia. We previously demonstrated that Ang II infusion in rodents results in skeletal muscle wasting and reduced muscle regenerative potential via Ang II type 1 receptor (AT1R) signaling, potentially contributing to cachexia in CHF and CKD. Contrary to AT1R signaling, we found that signaling via Ang II type 2 receptor (AT2R) potentiates skeletal muscle satellite cell (SC) differentiation and muscle regenerative potential. However, mechanisms whereby AT2R regulates SC differentiation and cachexia development remain unknown. In this study, we found that GSK3{beta} activity was significantly suppressed during SC differentiation, whereas it was retained in SCs with AT2R knockdown. AT2R knockdown leads to higher GSK3{beta} and decreased {beta}-catenin activities both in vitro and in vivo. Treatment with GSK3{beta} inhibitor BIO restored {beta}-catenin activity and differentiation capacity of SCs with AT2R knockdown. Conversely, transgenic overexpression of AT2R in SCs inhibited GSK3{beta}, associated with increased {beta}-catenin activity and SC myogenic capacity both in vitro and in vivo. Interestingly, AT2R expression in undifferentiated SCs was regulated post-transcriptionally. An increase in systemic Ang II blunted AT2R induction during muscle regeneration. However, overexpression of AT2R restored AT2R levels and myogenesis in vivo. Together, these data suggest that the AT2R/GSK3{beta}/{beta}- catenin signaling pathway could serve as a potential therapeutic target to promote muscle regenerative capacity in chronic disease conditions characterized by heightened activation of the renin-angiotensin system, such as CHF and CKD.

cell biology↗

bioRxiv2022

INSULIN-LIKE GROWTH FACTOR I REDUCES CORONARY ATHEROSCLEROSIS IN PIGS WITH FAMILIAL HYPERCHOLESTEROLEMIA

ObjectiveAlthough murine models of coronary atherosclerotic disease (CAD) have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We tested IGF-1 effects in atherosclerotic FH pigs to consider use of IGF-1 to treat CAD in humans. FH pigs were administered with IGF-1 for 6 months. Atherosclerosis was quantified by serial intravascular ultrasound (IVUS) and histology, plaque composition - by immunohistochemistry. We used spatial transcriptomics (ST) analysis to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ResultsIGF-1-injected FH pigs had 1.8-fold increase in total circulating IGF-1 levels compared to control. IGF-1 decreased relative coronary atheroma (IVUS) and lesion cross-sectional area (histology). IGF-1 induced vascular hypertrophy and reduced circulating triglycerides, markers of systemic oxidative stress and pro-atherogenic CXCL12 chemokine levels. IGF-1 increased fibrous cap thickness, and reduced necrotic core size, macrophage content, and cell apoptosis, changes consistent with promotion of a stable plaque phenotype. IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1s effect on atherosclerosis. ConclusionsIGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials. ST profiling of plaques provided novel insights into potential mechanisms.

cell biology↗