Cardioprotective Effects of Angiotensin 1‐7 in Heart Failure with Preserved Ejection Fraction (HFpEF)
Bibliographic record
Abstract
Background Heart failure with preserved ejection fraction (HFpEF) is a global public‐health epidemic which accounts for half of the heart failure cases. Various therapeutic approaches have been tested to block the activation of Renin Angiotensin System (RAS), including AT1R blockers (ARBs), Angiotensin converting enzyme (ACE) inhibitor (ACEi), and direct renin inhibitors (DRIs) with modest to negligible benefits. Discovery of ACE2, a novel homolog of ACE, has advanced our understanding of the RAS. ACE2 is a monocarboxypeptidase which degrades Ang II into Ang 1‐7, which works via the activation of Mas receptor. We have previously shown the critical role of Ang 1‐7/MasR signaling as a negative regulator of the Ang II/AT1R signaling. It has been well understood that the actions of Ang 1‐7 results in the production of nitric oxide (NO) through MAS1, where the imbalance in the level of NO is known to be involved in the development of HEpEF. Objective To determine the therapeutic role of Ang 1‐7 in HFpEF and identify the molecular mechanism related to its action. Methods and results To generate a murine model of HFpEF, male WT mice were subjected to HFD in addition to eNOS inhibition with L‐NAME (0.5 g l‐1 in drinking water) as described by Schiattarella and Hill et al. The murine model of HFpEF was validated using the non‐invasive transthoracic echocardiography and invasive pressure‐volume (PV) loop analyses, which exhibited diastolic dysfunction as well as cardiac hypertrophy. To evaluate the effects of Ang 1‐7 on HFpEF, animals were administered with either saline or Ang 1‐7 (24 ug/kg/day) for the duration of four weeks. Ang 1‐7 decreased the development of diastolic dysfunction induced by HFD + L‐NAME. Series of histological and functional analysis indicated that the HFpEF was primarily due to cardiac metabolic dysfunction. Molecular analyses using Western blotting, showed an increased expression of STAT3 in HFpEF group, which was reduced after 4 weeks of Ang 1‐7 administration. Furthermore, AMPK expression was significantly decreased in HFpEF group, which was improved after 4 weeks of Ang 1‐7 treatment. Conclusion Ang 1‐7 treatment attenuated the development of HFD + L‐NAME‐induced HFpEF, reduced cardiac hypertrophy, and improved metabolic function.
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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) | 0.001 | 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) | 0.001 | 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 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".