Daily Cardiology Research Analysis
Analyzed 82 papers and selected 3 impactful papers.
Summary
Three mechanistic studies advance cardiovascular biology and therapeutic concepts: matrix stiffness triggers liquid–liquid phase separation of EphB4 to activate YAP and drive pulmonary hypertension; cardiomyocyte ALDH1A2-dependent retinoic acid production protects against ischemia–reperfusion injury via RAR–BMP7 signaling; and HDL-mediated cholesterol efflux restores TGFβ signaling by altering lipid-raft partitioning, reversing macrophage-like transitions of vascular smooth muscle cells.
Research Themes
- Mechanotransduction and biomolecular condensates in vascular disease
- Retinoic acid metabolism as a cardioprotective axis in ischemia–reperfusion
- HDL functional therapeutics and plaque stabilization via TGFβ signaling restoration
Selected Articles
1. Liquid-liquid phase separation of EphB4 drives pulmonary hypertension via YAP activation.
Matrix stiffening induces liquid–liquid phase separation of EphB4’s intrinsically disordered C-terminus in PASMCs, forming condensates that release YAP from cytoplasmic restraint and drive proliferation. A retro-inverso peptide targeting EphB4’s IDR, delivered via VAPG-modified nanoparticles, inhibited LLPS and attenuated pulmonary hypertension in rats, establishing EphB4 phase separation as a druggable node.
Impact: This work links mechanotransduction to biomolecular condensates in vascular pathology and provides targetable proof-of-concept with peptide-nanoparticle therapy in vivo.
Clinical Implications: EphB4 phase separation represents a therapeutic target for pulmonary hypertension, suggesting development of IDR-directed inhibitors and delivery systems; translation will require human tissue validation and safety studies.
Key Findings
- EphB4 expression is upregulated in pulmonary hypertension; smooth muscle-specific EphB4 deficiency alleviates PH in rats.
- Matrix stiffening extends EphB4’s C-terminal IDR, inducing liquid–liquid phase separation and condensate formation.
- EphB4 condensates sequester YAP regulators (ANXA2, YWHA), promoting YAP nuclear translocation and PASMC proliferation.
- A retro-inverso peptide targeting EphB4’s IDR, delivered via VAPG-modified nanoparticles, inhibits LLPS and attenuates PH progression.
Methodological Strengths
- Integrated biophysical, cellular, genetic knockout, and in vivo rat models to establish causality.
- Therapeutic proof-of-concept using a retro-inverso peptide and targeted nanoparticle delivery.
Limitations
- Preclinical models; human validation of EphB4 LLPS and safety/PK of peptide-nanoparticle therapy are lacking.
- Long-term efficacy and potential off-target effects of EphB4 IDR inhibition remain unknown.
Future Directions: Validate EphB4 LLPS and the ANXA2/YWHA–YAP axis in human PH tissues; optimize IDR-directed inhibitors and delivery; evaluate safety and efficacy in large-animal models and early-phase clinical trials.
Vascular extracellular matrix stiffening is an early and pervasive driver of pulmonary hypertension (PH), though its mechanistic links to pathological cellular responses remain unclear. This study identifies Eph receptor B4 (EphB4), a receptor tyrosine kinase, as a key mediator of stiffness-induced responses in pulmonary artery smooth muscle cells (PASMCs). EphB4 was significantly upregulated in PH, and its smooth muscle-specific deficiency alleviated PH in rats. Matrix stiffening promoted conformational extension of the EphB4 C-terminal intrinsically disordered region (IDR), inducing its liquid-liquid phase separation (LLPS) into biomolecular condensates. These condensates sequestered Yes-associated protein (YAP)-regulating proteins, including ANXA2 and YWHA, disrupting YAP cytoplasmic retention and promoting its nuclear translocation to drive PASMC proliferation. Targeting the IDR of EphB4 with a retro-reversed peptide inhibited LLPS. Finally, delivering this peptide via VAPG-modified nanoparticles effectively attenuated PH progression. Our work establishes a novel EphB4-ANXA2/YWHA-YAP axis and highlights EphB4 phase separation as a promising therapeutic target for PH.
2. Identification of ALDH1A2-mediated cardioprotective benefits in myocardial ischaemia-reperfusion injury.
Cardiomyocyte ALDH1A2 was identified as a nodal regulator of ischemia–reperfusion injury: genetic ablation worsened dysfunction and fibrosis, whereas overexpression conferred robust protection by increasing retinoic acid production. RA engaged RARs to upregulate Bmp7, reducing cell death and cardiac fibrosis, positioning the ALDH1A2–RA–BMP7 axis as a therapeutic target.
Impact: This study pinpoints a metabolic enzyme as a central, genetically validated switch controlling RA-mediated cardioprotection after reperfusion, offering a precise molecular entry point for therapy.
Clinical Implications: Augmenting ALDH1A2 activity or RA–RAR–BMP7 signaling could reduce reperfusion injury and adverse remodeling post-PCI or CABG; translational work must balance RA’s systemic effects and optimize timing/dose.
Key Findings
- Transcriptomic profiling after MIR identified cardiomyocyte Aldh1a2 as a central regulator of I/R-induced dysfunction.
- Aldh1a2 knockout aggravated cardiac dysfunction, injury, and fibrosis; ALDH1A2 overexpression conferred protection in I/R.
- Cardioprotection depended on ALDH1A2-catalyzed retinoic acid production, which via RARs upregulated Bmp7 to suppress cell death and fibrosis.
Methodological Strengths
- Integrated unbiased transcriptomics with genetic loss- and gain-of-function in cardiomyocytes.
- In vivo ischemia–reperfusion models with mechanistic linkage to RA–RAR–BMP7 signaling.
Limitations
- Preclinical mouse models; large-animal and human data are lacking.
- Potential systemic effects of RA signaling may complicate translation without targeted delivery.
Future Directions: Develop small molecules or gene-regulatory tools to upregulate ALDH1A2; test RA–BMP7 augmentation in large-animal reperfusion models; delineate therapeutic window and safety profile.
AIMS: Myocardial ischaemia-reperfusion (MIR) injury is one of the major causes of poor prognosis after revascularization in myocardial infarction. Retinoic acid (RA) signalling is activated after myocardial infarction and participates in cardiac repair after myocardial infarction, but whether it can be applied to target MIR and the specific mechanism underlying its regulation and action in MIR remain unclear. METHODS AND RESULTS: We systematically analysed the changes of heart gene transcriptional profile post-MIR and identified cardiomyocyte Aldh1a2 as a central regulator in I/R-induced heart dysfunction. Compared to wild-type controls, Aldh1a2 ablation significantly aggravated heart dysfunction, myocardial damage and fibrosis, while overexpressing ALDH1A2 provided robust protection against heart injury in response to I/R surgery. The in-depth mechanistic investigations indicated that the cardioprotective role of ALDH1A2 is largely dependent on catalyzing RA production. The cardiomyocyte-generated RA inhibited cell death and cardiac fibrosis by binding to RA receptors and regulating the transcription of Bmp7. CONCLUSION: In summary, our study indicates that Aldh1a2 is the central RA-producing enzyme mediating the protective effect against MIR injury and the following cardiac remodelling. Potentiating Aldh1a2 transcription and the downstream RA signalling is a potential means of treatment against MIR injury.
3. HDL Regulates TGFβ-Receptor Lipid Raft Partitioning, Restoring Contractile Features of Cholesterol-Loaded Vascular Smooth Muscle Cells.
Cholesterol loading relocates TGFβ receptors into lipid rafts in VSMCs, dampening TGFβ signaling and promoting a macrophage-like phenotype. HDL-mediated cholesterol efflux restores receptor partitioning and TGFβ–Mir145 signaling, re-inducing Acta2 and suppressing CD68; ApoA1 infusion recapitulates these effects in atherosclerotic mice, suggesting HDL-centric strategies to stabilize plaques.
Impact: It mechanistically links cholesterol accumulation to TGFβ signaling compartmentalization and VSMC phenotypic switching and provides in vivo evidence that HDL/ApoA1 can reverse this process.
Clinical Implications: Enhancing HDL function or using ApoA1/HDL mimetics may reprogram plaque VSMCs toward a contractile state, potentially stabilizing atherosclerotic plaques; clinical translation requires demonstrating net benefit beyond lipid lowering.
Key Findings
- Cholesterol loading drives TGFβ receptors into membrane lipid rafts, downregulating TGFβ signaling in human VSMCs.
- HDL-mediated cholesterol efflux restores TGFβ signaling, increases Acta2, and suppresses CD68 via Mir145 enhancement.
- In atherosclerotic mice, ApoA1 administration increased VSMC Acta2 and reduced CD68, indicating in vivo phenotypic reversal.
Methodological Strengths
- Convergent in vitro mechanistic and in vivo translational evidence linking lipid rafts, TGFβ signaling, and VSMC phenotype.
- Use of ApoA1 administration to functionally test HDL-mediated reversal in an atherosclerosis model.
Limitations
- Human clinical data are lacking; plaque-level effects and outcomes remain untested.
- Past HDL-raising trials have had mixed results; efficacy may depend on HDL functionality and delivery.
Future Directions: Assess HDL/ApoA1 mimetics on VSMC phenotype and plaque stability in humans (biopsy/imaging); develop biomarkers of TGFβ-raft partitioning; test combination with lipid-lowering therapy.
Many cells identified as macrophage-like in human and mouse atherosclerotic plaques are thought to be of vascular smooth muscle cell (VSMC) origin. We identified cholesterol-mediated down-regulation of TGFβ signaling in vitro in human (h)VSMCs by localization of TGFβ receptors in membrane lipid rafts, which was reversed by high-density lipoprotein (HDL)-mediated cholesterol efflux. This restored VSMC contractile marker (Acta2) and suppressed macrophage marker (CD68) expression by promoting TGFβ enhancement of Mir145 expression. In vivo, administration of ApoA1 (which forms HDL) to atherosclerotic mice also promoted VSMC Acta2 expression and reduced CD68 expression. Because macrophage-like VSMCs are thought to have adverse properties, our studies not only show mechanistically how cholesterol causes their transition, but also suggest that efflux-competent HDL particles may have a therapeutic role by restoring a more favorable phenotypic state of VSMCs in atherosclerotic plaques.