Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts
Abstract Background High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplant...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-022-01573-x |
| _version_ | 1818504976347955200 |
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| author | Raffaele Marfella Nunzia D’Onofrio Gelsomina Mansueto Vincenzo Grimaldi Maria Consiglia Trotta Celestino Sardu Ferdinando Carlo Sasso Lucia Scisciola Cristiano Amarelli Salvatore Esposito Michele D’Amico Paolo Golino Marisa De Feo Giuseppe Signoriello Pasquale Paolisso Emanuele Gallinoro Marc Vanderheyden Ciro Maiello Maria Luisa Balestrieri Emanuele Barbato Claudio Napoli Giuseppe Paolisso |
| author_facet | Raffaele Marfella Nunzia D’Onofrio Gelsomina Mansueto Vincenzo Grimaldi Maria Consiglia Trotta Celestino Sardu Ferdinando Carlo Sasso Lucia Scisciola Cristiano Amarelli Salvatore Esposito Michele D’Amico Paolo Golino Marisa De Feo Giuseppe Signoriello Pasquale Paolisso Emanuele Gallinoro Marc Vanderheyden Ciro Maiello Maria Luisa Balestrieri Emanuele Barbato Claudio Napoli Giuseppe Paolisso |
| author_sort | Raffaele Marfella |
| collection | DOAJ |
| description | Abstract Background High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. Objectives We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1–9, Ang 1–7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. Methods We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1–9, Ang 1–7, MasR, NAFT, and fibrosis. Results GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1–9, Ang 1–7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. Conclusion Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. Trial registration: https://clinicaltrials.gov/ NCT03546062. |
| first_indexed | 2024-12-10T21:44:29Z |
| format | Article |
| id | doaj.art-8205c69318ef4c8fa6ce7570319743ed |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-12-10T21:44:29Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-8205c69318ef4c8fa6ce7570319743ed2022-12-22T01:32:24ZengBMCCardiovascular Diabetology1475-28402022-08-0121111410.1186/s12933-022-01573-xGlycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic heartsRaffaele Marfella0Nunzia D’Onofrio1Gelsomina Mansueto2Vincenzo Grimaldi3Maria Consiglia Trotta4Celestino Sardu5Ferdinando Carlo Sasso6Lucia Scisciola7Cristiano Amarelli8Salvatore Esposito9Michele D’Amico10Paolo Golino11Marisa De Feo12Giuseppe Signoriello13Pasquale Paolisso14Emanuele Gallinoro15Marc Vanderheyden16Ciro Maiello17Maria Luisa Balestrieri18Emanuele Barbato19Claudio Napoli20Giuseppe Paolisso21Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Department of Precision Medicine, The University of Campania “Luigi Vanvitelli”Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Unit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi HospitalUnit of Pathological Anatomy, Aversa HospitalDepartment of Experimental Medicine, University of Campania “Luigi Vanvitelli”Cardiology Division, University “L. Vanvitelli” - Monaldi HospitalDepartment of Cardio-Thoracic Sciences, University of Campania “Luigi Vanvitelli”Statistical Unit-Department of Mental Health and Public Medicine, University of Campania “Luigi Vanvitelli”Cardiovascular Center Aalst, OLV-ClinicCardiology Division, University “L. Vanvitelli” - Monaldi HospitalCardiovascular Center Aalst, OLV-ClinicUnit of Cardiac Surgery and Transplants, AORN Ospedali dei Colli-Monaldi HospitalDepartment of Experimental Medicine, University of Campania “Luigi Vanvitelli”Cardiovascular Center Aalst, OLV-ClinicDepartment of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”Abstract Background High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. Objectives We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1–9, Ang 1–7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. Methods We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1–9, Ang 1–7, MasR, NAFT, and fibrosis. Results GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1–9, Ang 1–7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. Conclusion Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. Trial registration: https://clinicaltrials.gov/ NCT03546062.https://doi.org/10.1186/s12933-022-01573-xHeart transplantationDiabetesHbA1cDiabetic cardiomyopathyRAS-inhibition therapy |
| spellingShingle | Raffaele Marfella Nunzia D’Onofrio Gelsomina Mansueto Vincenzo Grimaldi Maria Consiglia Trotta Celestino Sardu Ferdinando Carlo Sasso Lucia Scisciola Cristiano Amarelli Salvatore Esposito Michele D’Amico Paolo Golino Marisa De Feo Giuseppe Signoriello Pasquale Paolisso Emanuele Gallinoro Marc Vanderheyden Ciro Maiello Maria Luisa Balestrieri Emanuele Barbato Claudio Napoli Giuseppe Paolisso Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts Cardiovascular Diabetology Heart transplantation Diabetes HbA1c Diabetic cardiomyopathy RAS-inhibition therapy |
| title | Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts |
| title_full | Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts |
| title_fullStr | Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts |
| title_full_unstemmed | Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts |
| title_short | Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts |
| title_sort | glycated ace2 reduces anti remodeling effects of renin angiotensin system inhibition in human diabetic hearts |
| topic | Heart transplantation Diabetes HbA1c Diabetic cardiomyopathy RAS-inhibition therapy |
| url | https://doi.org/10.1186/s12933-022-01573-x |
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