Article ; Online: Beneficial effects of angiotensin-(1-7) against deoxycorticosterone acetate-induced diastolic dysfunction occur independently of changes in blood pressure.
Hypertension (Dallas, Tex. : 1979)
2015 Volume 66, Issue 2, Page(s) 389–395
Abstract: ... signaling against DOCA-induced diastolic dysfunction occurs independently of BP attenuation and is mediated ... heart failure. On the contrary, angiotensin (Ang)-(1-7) has emerged as a potential strategy for treatment of cardiac dysfunction ... of Ang-(1-7) in hypertensive models is its dependence on blood pressure (BP) reduction. Here ...
| Abstract | Mineralocorticoids have been implicated in the pathogenesis of diastolic heart failure. On the contrary, angiotensin (Ang)-(1-7) has emerged as a potential strategy for treatment of cardiac dysfunction induced by excessive mineralocorticoid receptor activation. A critical question about the cardioprotective effect of Ang-(1-7) in hypertensive models is its dependence on blood pressure (BP) reduction. Here, we addressed this question by investigating the mechanisms involved in Ang-(1-7) cardioprotection against mineralocorticoid receptor activation. Sprague-Dawley (SD) and transgenic (TG) rats that overexpress an Ang-(1-7) producing fusion protein (TG(A1-7)3292) were treated with deoxycorticosterone acetate (DOCA) for 6 weeks. After treatment, SD rats became hypertensive and developed ventricular hypertrophy. These parameters were attenuated in TG-DOCA. SD-DOCA rats developed diastolic dysfunction which was associated at the cellular level with reduced Ca(2+) transient. Oppositely, TG-DOCA myocytes presented enhanced Ca(2+) transient. Moreover, higher extracellular signal-regulated kinase phosphorylation, type 1 phosphatase, and protein kinase Cα levels were found in SD-DOCA cells. In vivo, pressor effects of DOCA can contribute to the diastolic dysfunction, raising the question of whether protection in TG was a consequence of reduced BP. To address this issue, BP in SD-DOCA was kept at TG-DOCA level by giving hydralazine or by reducing the DOCA amount given to rats (Low-DOCA). Under similar BP, diastolic dysfunction and molecular changes were still evident in DOCA-hydralazine and SD-low-DOCA, but not in TG-DOCA. In conclusion, Ang-(1-7) protective signaling against DOCA-induced diastolic dysfunction occurs independently of BP attenuation and is mediated by the activation of pathways involved in Ca(2+) handling, hypertrophy, and survival. |
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| MeSH term(s) | Angiotensin I/pharmacology ; Angiotensin I/therapeutic use ; Animals ; Blood Pressure/drug effects ; Blood Pressure/physiology ; Calcium/physiology ; Calcium Signaling/drug effects ; Calcium Signaling/physiology ; Desoxycorticosterone Acetate/adverse effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Heart Failure, Diastolic/chemically induced ; Heart Failure, Diastolic/physiopathology ; Heart Failure, Diastolic/prevention & control ; Hydralazine/pharmacology ; Hypertension/physiopathology ; Male ; Peptide Fragments/pharmacology ; Peptide Fragments/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic | |||||
| Chemical Substances | Peptide Fragments ; Hydralazine (26NAK24LS8) ; Desoxycorticosterone Acetate (6E0A168OB8) ; Angiotensin I (9041-90-1) ; angiotensin I (1-7) (IJ3FUK8MOF) ; Calcium (SY7Q814VUP) | |||||
| Language | English | |||||
| Publishing date | 2015-08 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 423736-5 | |||||
| ISSN | 1524-4563 ; 0194-911X ; 0362-4323 | |||||
| ISSN (online) | 1524-4563 | |||||
| ISSN | 0194-911X ; 0362-4323 | |||||
| DOI | 10.1161/HYPERTENSIONAHA.114.04893 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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