Abstract 071: Cytokine-angiotensin II Interplay in Cyclophilin D-mediated Vascular Oxidative Stress and Hypertension
Bibliographic record
Abstract
Vascular inflammation and oxidative stress interact in a feed-forward fashion to promote vascular disease and hypertension. We hypothesized that angiotensin II and inflammatory cytokines encountered in hypertension co-operatively induce superoxide (O 2 • - ) production by mitochondrial complex I and that efforts to reduce complex I O 2 • - will reduce hypertension. Treatment of human aortic endothelial cells in culture with angiotensin II (10 nM), IL17A (10 nM) and TNFα (1 nM), factors known to contribute to the hypertensive milieu, co-operatively induced mitochondrial O 2 • - from 340 to 958 pmol/mg protein as measured by HPLC and MitoSOX. This response was abolished by the complex I inhibitor rotenone. We further tested a potential role of Cyclophilin D (CypD), the redox sensitive regulatory subunit of the mitochondrial transition pore in complex I O 2 • - production. Both the specific CypD inhibitor Sanglifehrin A and knockdown of CypD by siRNA prevented endothelial cell O 2 • - production in response to Ang/IL17/TNF. We also found that this cytokine-angiotensin II milieu induced S-glutathionylation of CypD and that scavenging mitochondrial H 2 O 2 with mitoEbselen prevents this and eliminates CypD dependent complex I O 2 • - production. We further studied the functional role of oxidative stress induced by Ang/IL17/TNF in isometric tension studies of mouse aortic rings. Twenty-four hour treatment of organoid cultured vessels with AngII/IL17/TNF reduced endothelium-dependent vasodilatation to acetylcholine and this was prevented by knockdown of CypD and was not observed in vessels of mice with overexpression of mitochondrial SOD or mitochondrial catalase. The in vivo role of CypD in regulation of vascular O 2 • - and blood pressure was further studied in mice infused with angiotensin II (490 ng/kg/min). Treatment with Sanglifehrin A after the onset of hypertension reduced blood pressure from 162 to 133 mmHg (P<0.01), reduced vascular O 2 • - and improved endothelium-dependent vasodilation. These studies have defined a novel role of Cyclophilin D as a cause of vascular dysfunction and hypertension and have provided a new target for treatment of this disease.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".