Biology subjects

Libby, P.

Publications and source records attributed to Libby, P..

4 recordsLinked to original sources

bioRxiv2025

Selective PPAR-α activation with pemafibrate attenuates macrophage-mediated progression of calcific aortic valve disease

BACKGROUNDCalcific aortic valve disease (CAVD) compromises valve compliance and cardiac hemodynamics leading to aortic stenosis (AS) and cardiovascular dysfunction. With treatment for severe AS limited to valve replacement and no effective pharmacotherapies, new interventions are urgently needed for patients. This study evaluated pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPAR) activator as a novel therapeutic for CAVD and AS. METHODS AND RESULTSIn an aortic valve wire injury (AVWI) model of AS in Ldlr-/- mice, pemafibrate administration (0.2 mg/kg/day) for 15 weeks improved aortic valve function and reduced valvular calcification by 39% (p<0.001), accompanied by reduced leaflet inflammation and CD68 macrophage infiltration. These effects were independent of changes in plasma triglyceride levels. In vitro, pemafibrate suppressed inflammation-mediated calcification of primary human valvular interstitial cells (VICs) by modulating macrophage-derived secreted factors, identifying macrophage-VIC crosstalk as a key disease mechanism. Direct treatment of macrophages with pemafibrate, or exposure to serum from pemafibrate-treated participants in the PROMINENT randomized controlled trial, shifted macrophages toward a less inflammatory and less chemotactic phenotype. Proteomic analyses of patient serum substantiated these findings by reflecting a systemic reduction in inflammatory parameters and monocyte activation. Network integration of the in vitro derived pemafibrate-responsive proteome with human calcified AV tissue proteomes identified aberrant protein translation (GNB2L1, GSPT1) and disrupted bioenergetics (MYDGF, PDIA4) as potential clinically relevant pemafibrate-responsive pathways and effector proteins relevant to AS progression. CONCLUSIONSPemafibrate slows experimental AS progression and valve calcification through modulation of macrophage-VIC crosstalk, independent of lipid lowering. These findings support further evaluation of pemafibrate as a potential pharmacological approach for CAVD and support further testing in randomized clinical trials.

pharmacology and toxicology↗

bioRxiv2025

Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2-deficient CHIP via XPO1 Inhibition and Atf3 restoration

TET2 is the second most frequently mutated gene in clonal hematopoiesis of indeterminate potential (CHIP), driving hematopoietic stem cell clonal expansion and increasing the risk of myeloid malignancies. Affected individuals often develop atherosclerotic cardiovascular disease, exacerbated by hyperinflammatory TET2-mutant macrophages. Here, we show that the XPO1 nuclear export inhibitor eltanexor significantly reduces atherosclerotic plaque formation in a mouse model of Tet2-mutant CHIP. In addition, we investigated the mechanisms and gene expression pathways that underlie the proinflammatory phenotype that characterizes Tet2-mutant CHIP. Single-cell CITE-seq identified increased expression of multiple proinflammatory mediators in Tet2-mutant macrophages and in non-hematopoietic cells of the aortic wall, which was reduced by eltanexor treatment. Atf3, which encodes a core transcriptional modulator of inflammation, occupies and regulates the largest enhancer in wild-type macrophages. Tet2 loss diminished ATF3 binding to the regulatory loci of inflammatory mediators, which was restored upon XPO1 inhibition. These results provide new insights into drivers of heightened inflammation in TET2-mutant CHIP and highlight a novel therapeutic strategy for intervention.

immunology↗

bioRxiv2023

Human Plasma Proteomic Profile of Clonal Hematopoiesis

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

genetics↗

bioRxiv2019

A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques

Endothelial erosion of atherosclerotic plaques and resulting thrombosis causes approximately 30% of acute coronary syndromes (ACS). As changes in the haemodynamic environment strongly influence endothelial function and contribute to plaque development, we reconstructed the coronary artery geometries of plaques with thrombi overlying intact fibrous caps from 17 ACS patients and performed computational fluid dynamic analysis. The results demonstrated that erosions frequently occur within areas of stenosis exposed to elevated flow. We recapitulated this flow environment in vitro, exposing human coronary artery endothelial cells to elevated flow and modelled smoking (a risk factor for erosion) by exposure to a combination of aqueous cigarette smoke extract and TNF. This treatment induced endothelial detachment, which increased with pharmacological activation of the antioxidant system controlled by transcription factor Nrf2 (encoded by NFE2L2). The expression of Oxidative Stress Growth INhibitor genes OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Overexpression of either Nrf2 or OSGIN1+2 induced cell detachment, which did not depend on apoptosis, and could be partially rescued by inhibition of HSP70 using VER-155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smoking-induced hyperactivation of Nrf2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.

cell biology↗