Daily Cardiology Research Analysis
Mechanistic studies uncovered new drivers of atherogenesis and endothelial dysfunction, while a large clinical cohort clarified that residual inflammatory risk—not triglycerides—dominates post-PCI events despite well-controlled LDL cholesterol. Specifically, erythrocyte-derived extracellular vesicles transfer arginase-1 to endothelium in type 2 diabetes, and macrophage HM13/SPP promotes foamy macrophage formation and atherosclerosis by degrading HO-1.
Summary
Mechanistic studies uncovered new drivers of atherogenesis and endothelial dysfunction, while a large clinical cohort clarified that residual inflammatory risk—not triglycerides—dominates post-PCI events despite well-controlled LDL cholesterol. Specifically, erythrocyte-derived extracellular vesicles transfer arginase-1 to endothelium in type 2 diabetes, and macrophage HM13/SPP promotes foamy macrophage formation and atherosclerosis by degrading HO-1.
Research Themes
- Endothelial dysfunction mechanisms in diabetes
- Atherogenesis via ER proteostasis and macrophage biology
- Residual inflammatory risk after PCI despite LDL control
Selected Articles
1. Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes.
Using RBC-derived extracellular vesicles from T2D patients, the authors show that EV cargoed arginase-1 is transferred to endothelial cells, increasing oxidative stress and impairing endothelium-dependent relaxation. Inhibition of arginase (within EVs or vascular) or oxidative stress mitigated dysfunction, implicating RBC-EVs as key mediators of diabetic endothelial injury.
Impact: This study defines a concrete, targetable mechanism linking erythrocytes to vascular dysfunction in T2D via EV transfer of arginase-1. It opens therapeutic avenues for arginase inhibition or EV uptake modulation to restore endothelial health.
Clinical Implications: Arginase-1 and EV-mediated signaling emerge as therapeutic targets to improve endothelial function in T2D; arginase inhibitors or strategies reducing RBC-EV uptake could complement standard cardiometabolic care.
Key Findings
- T2D RBC-derived EVs are taken up more avidly by endothelial cells despite lower EV production.
- T2D RBC-EVs impair endothelium-dependent relaxation; arginase inhibition (in EVs or vessel) and antioxidant strategies attenuate dysfunction.
- Arginase-1 is present in RBC-EVs and increases in endothelial cells after exposure, even with endothelial Arg1 mRNA silencing and in Arg1-deficient endothelium.
- Mechanism involves EV transfer of arginase-1 leading to oxidative stress and endothelial dysfunction.
Methodological Strengths
- Use of human patient-derived RBC-EVs with functional endothelial assays and vasoreactivity testing.
- Genetic validation using endothelial Arg1-knockout mice to confirm EV-mediated protein transfer effects.
Limitations
- Clinical donor sample size and heterogeneity are not detailed in the abstract; translational dosing and pharmacology require further study.
- Predominantly ex vivo/in vitro mechanistic work; in vivo therapeutic modulation of EV pathways was not reported.
Future Directions: Evaluate arginase inhibition and EV uptake blockade in vivo for vascular endpoints in T2D, and test circulating RBC-EV arginase-1 as a biomarker of endothelial risk.
2. Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis.
Network analysis and mechanistic studies identify HM13/SPP as a macrophage driver of lipid loading and foamy cell formation by promoting ERAD-dependent degradation of HO-1. Myeloid HM13 overexpression accelerates atherosclerosis, whereas knockout is protective; AIP suppresses HM13 via AHR–p38–c-JUN signaling.
Impact: Reveals a previously unrecognized ERAD–HO-1 axis in foamy macrophage biology and atherogenesis, nominating HM13/SPP as a targetable node downstream of AIP/AHR signaling.
Clinical Implications: Therapeutic modulation of HM13/SPP or reinforcement of HO-1 stability may reduce foam cell burden and atherosclerosis; AHR–AIP pathway tuning could offer anti-atherogenic strategies.
Key Findings
- AIP negatively correlates with HM13/SPP in human atherosclerosis (STAGE cohort), oxLDL-treated macrophages, and plaque foam cells.
- AIP via AHR chaperoning inhibits p38–c-JUN-mediated HM13 transactivation, reducing macrophage lipid accumulation.
- Myeloid HM13/SPP overexpression increases foam cell formation and atherogenesis in vivo; knockout has opposite, protective effects.
- HM13/SPP promotes ERAD-dependent proteasomal degradation of HO-1, linking ER proteostasis to foam cell biology.
Methodological Strengths
- Integrates patient transcriptomics (WGCNA) with in vitro and in vivo myeloid-specific gain- and loss-of-function models.
- Mechanistic dissection of signaling (AHR–p38–c-JUN) and ERAD–HO-1 pathway with multi-level validation.
Limitations
- Pharmacologic HM13/SPP inhibition was not tested; off-target or systemic effects remain to be characterized.
- Translational validation in human intervention studies is lacking.
Future Directions: Develop selective HM13/SPP inhibitors or HO-1 stabilizers; assess efficacy in preclinical atherosclerosis models and explore AHR–AIP pathway modulation in humans.
3. Prognostic impact of residual inflammatory and triglyceride risk in statin-treated patients with well-controlled LDL cholesterol and atherosclerotic cardiovascular disease.
In 9,446 statin-treated PCI patients with LDL-C <70 mg/dL, elevated hs-CRP (≥2 mg/L) with or without TG elevation predicted higher 1-year MACE, driven largely by all-cause mortality. Isolated residual TG risk did not increase events, underscoring inflammation—not triglycerides—as the dominant residual risk.
Impact: Shifts risk stratification focus beyond LDL to inflammation in a large, contemporary PCI cohort, informing prioritization of anti-inflammatory prevention strategies.
Clinical Implications: Consider hs-CRP to identify high-risk patients despite LDL control and evaluate anti-inflammatory interventions; isolated hypertriglyceridemia may warrant individualized decisions rather than broad escalation.
Key Findings
- Among statin-treated PCI patients with LDL-C <70 mg/dL, 31.9% had residual inflammatory risk and 5.7% had combined TG+inflammatory risk.
- Residual inflammatory risk (hs-CRP ≥2 mg/L), alone or combined with elevated TGs, was associated with higher 1-year MACE after multivariable adjustment, mainly driven by all-cause mortality.
- Isolated residual TG risk (TG ≥150 mg/dL with hs-CRP <2 mg/L) did not differ from no residual risk in MACE.
Methodological Strengths
- Large, real-world cohort with contemporary PCI and strict LDL-C threshold (<70 mg/dL).
- Multivariable Cox modeling with clear risk group definitions using hs-CRP and TG.
Limitations
- Observational design with potential residual confounding; single time-point biomarker assessment.
- Generalizability beyond PCI populations and to non-statin therapies requires caution.
Future Directions: Prospective trials testing anti-inflammatory therapies in post-PCI patients with elevated hs-CRP despite LDL control; evaluate dynamic hs-CRP trajectories and multi-marker panels.