{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T09:42:11Z","timestamp":1774604531626,"version":"3.50.1"},"reference-count":70,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T00:00:00Z","timestamp":1683849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH NHLBI","award":["R01HL138988-01A1"],"award-info":[{"award-number":["R01HL138988-01A1"]}]},{"name":"NIH NHLBI","award":["K99\/R00HL121152"],"award-info":[{"award-number":["K99\/R00HL121152"]}]},{"name":"NIH NHLBI","award":["932792"],"award-info":[{"award-number":["932792"]}]},{"name":"NIH","award":["R01HL138988-01A1"],"award-info":[{"award-number":["R01HL138988-01A1"]}]},{"name":"NIH","award":["K99\/R00HL121152"],"award-info":[{"award-number":["K99\/R00HL121152"]}]},{"name":"NIH","award":["932792"],"award-info":[{"award-number":["932792"]}]},{"name":"American Heart Association CDA","award":["R01HL138988-01A1"],"award-info":[{"award-number":["R01HL138988-01A1"]}]},{"name":"American Heart Association CDA","award":["K99\/R00HL121152"],"award-info":[{"award-number":["K99\/R00HL121152"]}]},{"name":"American Heart Association CDA","award":["932792"],"award-info":[{"award-number":["932792"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Obese and pre-diabetic women have a higher risk for cardiovascular death than age-matched men with the same symptoms, and there are no effective treatments. We reported that obese and pre-diabetic female Zucker Diabetic Fatty (ZDF-F) rats recapitulate metabolic and cardiac pathology of young obese and pre-diabetic women and exhibit suppression of cardio-reparative AT2R. Here, we investigated whether NP-6A4, a new AT2R agonist with the FDA designation for pediatric cardiomyopathy, mitigate heart disease in ZDF-F rats by restoring AT2R expression. Methods: ZDF-F rats on a high-fat diet (to induce hyperglycemia) were treated with saline, NP-6A4 (10 mg\/kg\/day), or NP-6A4 + PD123319 (AT2R-specific antagonist, 5 mg\/kg\/day) for 4 weeks (n = 21). Cardiac functions, structure, and signaling were assessed by echocardiography, histology, immunohistochemistry, immunoblotting, and cardiac proteome analysis. Results: NP-6A4 treatment attenuated cardiac dysfunction, microvascular damage (\u2212625%) and cardiomyocyte hypertrophy (\u2212263%), and increased capillary density (200%) and AT2R expression (240%) (p &lt; 0.05). NP-6A4 activated a new 8-protein autophagy network and increased autophagy marker LC3-II but suppressed autophagy receptor p62 and autophagy inhibitor Rubicon. Co-treatment with AT2R antagonist PD123319 suppressed NP-6A4\u2019s protective effects, confirming that NP-6A4 acts through AT2R. NP-6A4-AT2R-induced cardioprotection was independent of changes in body weight, hyperglycemia, hyperinsulinemia, or blood pressure. Conclusions: Cardiac autophagy impairment underlies heart disease induced by obesity and pre-diabetes, and there are no drugs to re-activate autophagy. We propose that NP-6A4 can be an effective drug to reactivate cardiac autophagy and treat obesity- and pre-diabetes-induced heart disease, particularly for young and obese women.<\/jats:p>","DOI":"10.3390\/cells12101373","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T09:26:13Z","timestamp":1683883573000},"page":"1373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes"],"prefix":"10.3390","volume":"12","author":[{"given":"Anthony M.","family":"Belenchia","sequence":"first","affiliation":[{"name":"Dalton Cardiovascular Research Center and Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asma","family":"Boukhalfa","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent G.","family":"DeMarco","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Mehm","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abuzar","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Brandeis University, Waltham, MA 02453, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Liu","sequence":"additional","affiliation":[{"name":"Charles W. Gehrke Proteomics Center, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinian","family":"Tang","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhavi P.","family":"Gavini","sequence":"additional","affiliation":[{"name":"Novopyxis Inc., Boston, MA 02108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Mooney","sequence":"additional","affiliation":[{"name":"Charles W. Gehrke Proteomics Center, University of Missouri, Columbia, MO 65211, USA"},{"name":"Division of Biochemistry, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard H.","family":"Chen","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lakshmi","family":"Pulakat","sequence":"additional","affiliation":[{"name":"Dalton Cardiovascular Research Center and Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA"},{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USA"},{"name":"Department of Medicine, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e005375","DOI":"10.1161\/CIRCOUTCOMES.118.005375","article-title":"Mortality From Ischemic Heart Disease","volume":"12","author":"Nowbar","year":"2019","journal-title":"Circ Cardiovasc. 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