P719Endothelial expression of adenylate cyclase type 9 (Adcy9) regulates endothelial cell signalling and vasodilation
Bibliographic record
Abstract
Abstract Background/Introduction The clinical benefits of the cholesterol ester transfer protein (CETP) inhibitor dalcetrapib are dependent on the ADCY9 gene, which encodes adenylate cyclase (AC) type 9 (AC9). AC9 is one of nine membrane-bound isoforms of AC producing cyclic adenosine monophosphate (cAMP). We demonstrated that Adcy9 inactivation in the mouse protects from atherosclerosis, but only in absence of CETP. Adcy9 inactivation is also associated with improved endothelial function, including greater endothelial-dependent vasodilation (EDV) in response to acetylcholine (ACh). This suggests that Adcy9 may control endothelial Ca2+, an essential mediator of endothelial cell (EC) signalling. We hypothesized that Adcy9 is expressed in the endothelium and controls EC signalling. Purpose Our aim was to study AC9 expression in the vascular endothelium and the role of AC9 expression on endothelial cAMP signalling and Ca2+ dynamics. Methods The effects of Adcy9 inactivation were studied using wild-type (WT) and Adcy9-inactivated (Adcy9Gt/Gt) mice and siRNA-mediated inactivation of ADCY9 in human coronary artery endothelial cells (HCAEC). In the mouse, AC9 expression was quantified in whole aorta (± endothelium) and primary cultures of lung EC (LEC) by Western blot. Endothelial Ca2+ pulsars were monitored in mouse femoral arteries in response to acetylcholine (ACh, 10 μM). cAMP accumulation to AC activators VIP and forskolin were measured in LEC and HCAEC. EDV to VIP was studied ex vivo in mouse femoral arteries using pressurized arteriography. Results AC9 is expressed in LEC and the aorta, and its detection in the latter decreased by 33% after mechanical removal of the endothelium (P<0.05). AC activation with forskolin (10–4 M) in LEC led to increased cAMP accumulation in response to Adcy9 inactivation (WT: 1129±138 pmol cAMP/mg of protein, Adcy9Gt/Gt: 1965±169, n=3; P<0.01). ADCY9 inactivation in HCAEC also increased cAMP accumulation to forskolin 10–4M (control siRNA: 85±17, ADCY9 siRNA: 150±6, n=3; P<0.01). In LEC, receptor-dependent accumulation of cAMP to VIP (10–5 M) was higher in Adcy9Gt/Gt (1509±258)) compared to WT (915±170, n=3; P<0.05) mice. In mouse femoral arteries, VIP-induced maximal vasodilation was increased by Adcy9 inactivation in the presence of the endothelium (Adcy9Gt/Gt: 85±4%, n=6; WT: 52±9%, n=5, P<0.05), but not in its absence (Adcy9Gt/Gt: 67±12%, n=6 and WT: 59±15%, n=5). In the femoral artery endothelium, ACh increased Ca2+ pulsar frequency more in Adcy9Gt/Gt (243±32%, n=4) than in WT (178±19%, n=5; P<0.05) mice. Conclusion ADCY9 is expressed in the endothelium, and its inactivation potentiates endothelial cell Ca2+ dynamics, cAMP accumulation and VIP-induced vasodilation. We therefore identify ADCY9 as a new molecular pathway regulating endothelial-dependent vasodilation. This suggests that ADCY9's endothelial biology could be involved in the ADCY9 genotype-dependent clinical effects of dalcetrapib. Acknowledgement/Funding DalCor
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".