Immune activation caused by vascular oxidation promotes fibrosis and hypertension.
Level 5 - mechanism / opinion, no new human data
Preclinical animal models and correlational human tissue analysis
PubMed 26595812 · doi:10.1172/JCI80761
What was done
Researchers evaluated mouse models of vascular oxidative stress: smooth muscle-specific overexpression of p22phox (tg(sm/p22phox)) and vascular-specific knockout of extracellular superoxide dismutase. They measured vascular collagen, aortic stiffening, renal function, blood pressure, cytokine levels, and isoketal-protein adducts in aortas, dendritic cells (DCs), and macrophages. To determine immune involvement, tg(sm/p22phox) mice were crossed with lymphocyte-deficient Rag1(-/-) mice, followed by adoptive T-cell transfer. Therapeutic testing evaluated the superoxide scavenger tempol and the isoketal scavenger 2-hydroxybenzylamine (2-HOBA). Isoketal adduct levels were also assessed in human aortic specimens.
What was found
Mice with vascular oxidative stress developed age-dependent vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension. T cells showed elevated IL-17A and IFN-γ production. Lymphocyte deficiency (Rag1(-/-)) prevented these phenotypes, while adoptive T-cell transfer restored them. Isoketal-protein adducts were elevated in tg(sm/p22phox) aortas, DCs, and macrophages; autologous DC pulsing with aortic homogenates stimulated T-cell proliferation and cytokine release (IFN-γ, IL-17A, TNF-α). Treatment with tempol or 2-HOBA normalized blood pressure, prevented DC/T-cell activation, and inhibited vascular inflammation and stiffening. In human aortas, isoketal content correlated with inflammation and fibrosis severity. The abstract reports no quantitative values.
Why it matters
This study defines a direct mechanistic pathway connecting vascular oxidative stress to immune-mediated vascular remodeling and hypertension. It identifies isoketal-protein adducts as potential targets for therapeutic scavenging in inflammatory vascular disease.
Limits
The abstract does not provide sample sizes, effect sizes, or confidence intervals. The interventional findings are restricted to mouse models, and human data are limited to correlational tissue measurements.
Cited by
- supports 2-hydroxybenzylamine (2-HOBA), a compound studied for treating hypertension via immune-vascular signaling, is found in only one food: Tartary buckwheat.