Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes
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 y...
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MDPI AG
2023-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/10/1373 |
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| author | Anthony M. Belenchia Asma Boukhalfa Vincent G. DeMarco Alexander Mehm Abuzar Mahmood Pei Liu Yinian Tang Madhavi P. Gavini Brian Mooney Howard H. Chen Lakshmi Pulakat |
| author_facet | Anthony M. Belenchia Asma Boukhalfa Vincent G. DeMarco Alexander Mehm Abuzar Mahmood Pei Liu Yinian Tang Madhavi P. Gavini Brian Mooney Howard H. Chen Lakshmi Pulakat |
| author_sort | Anthony M. Belenchia |
| collection | DOAJ |
| description | 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 (−625%) and cardiomyocyte hypertrophy (−263%), and increased capillary density (200%) and AT2R expression (240%) (<i>p</i> < 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’s 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. |
| first_indexed | 2024-03-11T03:52:14Z |
| format | Article |
| id | doaj.art-e720008f1c324294bf0e11216481236e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T03:52:14Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e720008f1c324294bf0e11216481236e2023-11-18T00:52:38ZengMDPI AGCells2073-44092023-05-011210137310.3390/cells12101373Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-DiabetesAnthony M. Belenchia0Asma Boukhalfa1Vincent G. DeMarco2Alexander Mehm3Abuzar Mahmood4Pei Liu5Yinian Tang6Madhavi P. Gavini7Brian Mooney8Howard H. Chen9Lakshmi Pulakat10Dalton Cardiovascular Research Center and Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USAMolecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USADepartment of Medicine, University of Missouri, Columbia, MO 65212, USAMolecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USADepartment of Neuroscience, Brandeis University, Waltham, MA 02453, USACharles W. Gehrke Proteomics Center, University of Missouri, Columbia, MO 65211, USAMolecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USANovopyxis Inc., Boston, MA 02108, USACharles W. Gehrke Proteomics Center, University of Missouri, Columbia, MO 65211, USAMolecular Cardiology Research Institute, Tufts Medical Center, and Department of Medicine, Tufts University, Boston, MA 02111, USADalton Cardiovascular Research Center and Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USABackground: 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 (−625%) and cardiomyocyte hypertrophy (−263%), and increased capillary density (200%) and AT2R expression (240%) (<i>p</i> < 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’s 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.https://www.mdpi.com/2073-4409/12/10/1373cardiovascular disease (CVD)body mass index (BMI)Angiotensin II receptor AT2 (AT2R)Zucker diabetic fatty-female (ZDF-F)Zucker diabetic fatty-male (ZDF-M)Zucker lean-female (ZL-F) |
| spellingShingle | Anthony M. Belenchia Asma Boukhalfa Vincent G. DeMarco Alexander Mehm Abuzar Mahmood Pei Liu Yinian Tang Madhavi P. Gavini Brian Mooney Howard H. Chen Lakshmi Pulakat Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes Cells cardiovascular disease (CVD) body mass index (BMI) Angiotensin II receptor AT2 (AT2R) Zucker diabetic fatty-female (ZDF-F) Zucker diabetic fatty-male (ZDF-M) Zucker lean-female (ZL-F) |
| title | Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes |
| title_full | Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes |
| title_fullStr | Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes |
| title_full_unstemmed | Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes |
| title_short | Cardiovascular Protective Effects of NP-6A4, a Drug with the FDA Designation for Pediatric Cardiomyopathy, in Female Rats with Obesity and Pre-Diabetes |
| title_sort | cardiovascular protective effects of np 6a4 a drug with the fda designation for pediatric cardiomyopathy in female rats with obesity and pre diabetes |
| topic | cardiovascular disease (CVD) body mass index (BMI) Angiotensin II receptor AT2 (AT2R) Zucker diabetic fatty-female (ZDF-F) Zucker diabetic fatty-male (ZDF-M) Zucker lean-female (ZL-F) |
| url | https://www.mdpi.com/2073-4409/12/10/1373 |
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