A Novel Role for Calpain in the Endothelial Dysfunction Induced by Activation of Angiotensin II Type 1 Receptor Signaling
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Bibliographic record
Abstract
RATIONALE: The cytosolic protease calpain has been recently implicated in the vascular remodeling of angiotensin II (Ang II) type 1 receptor (AT(1)R) signaling. The role of Ang II/AT(1)R/calpain signaling on endothelial function, an important and early determinant of vascular pathology, remains though totally unknown. Accordingly, we investigated the role of calpain in the endothelial dysfunction of Ang II. OBJECTIVE: To demonstrate a mechanistic role for calpain in the endothelial dysfunction induced by Ang II/AT(1)R signaling. To establish endothelial-expressed calpains as an important target of AT(1)R signaling. METHODS AND RESULTS: Subchronic administration of nonpressor doses of Ang II to rats and mice significantly increased vascular calpain activity via AT(1)R signaling. Intravital microscopy studies revealed that activation of vascular expressed calpains causes endothelial dysfunction with increased leukocyte-endothelium interactions and albumin permeability in the microcirculation. Western blot and immunohistochemistry studies confirmed that Ang II/AT(1)R signaling preferentially activates the constitutively expressed μ-calpain isoform and demonstrated a calpain-dependent degradation of IκBα, along with upregulation of nuclear factor κB-regulated endothelial cell adhesion molecules. These physiological and biochemical parameters were nearly normalized following inhibition of AT(1)R or calpain in vivo. RNA silencing studies in microvascular endothelial cells, along with knockout and transgenic mouse studies, further confirmed the role of μ-calpain in the endothelial adhesiveness induced by Ang II. CONCLUSIONS: This study uncovers a novel role for calpain in the endothelial dysfunction of Ang II/AT(1)R signaling and establishes the calpain system as a novel molecular target of the vascular protective action of renin-angiotensin system inhibition. Our results may have significant clinical implications in vascular disease.
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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 | 0.001 | 0.000 |
| 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 it