Angiotensin-(1-12)/chymase axis modulates cardiomyocyte L-type calcium currents in rats expressing human angiotensinogen.
Int J Cardiol
; 297: 104-110, 2019 12 15.
Article
em En
| MEDLINE
| ID: mdl-31629566
ABSTRACT
BACKGROUND:
Activation of the intracrine renin angiotensin systems (RAS) is increasingly recognized as contributing to human pathologies, yet non-canonical renin-independent mechanisms for angiotensin II (Ang II) biosynthesis remain controversial. Direct Ang II generation from angiotensin-(1-12) [Ang-(1-12)] by chymase is an essential intracrine source for regulation of cardiac function. Using a transgenic rat model that overexpresses the human angiotensinogen gene [TGR(hAGT)L1623] and displays increased cardiac Ang II levels, this study aimed to provide evidence for intracrine activation of L-type calcium currents (ICa-L) mediated by the Ang-(1-12)/chymase axis. METHODS ANDRESULTS:
On patch clamp, ICa-L density was significantly higher in TGR(hAGT)L1623 (-6.4⯱â¯0.3â¯pA/pF) compared to Sprague Dawley (SD) cardiomyocytes (-4.8, ± 0.5â¯pA/pF). Intracellular administration of Ang II and Ang-(1-12) elicited a ICa-L increase in both SD and TGR(hAGT)L1623 cardiomyocytes, albeit blunted in transgenic cells. ICa-L activation by intracellular Ang II and Ang-(1-12) was abolished by the specific Ang II type 1 receptor blocker E-3174. Co-administration of a chymase inhibitor prevented activation of ICa-L by Ang-(1-12). Confocal micrographs revealed abundant chymase (mast cell protease 5) immunoreactive protein in SD and TGR(hAGT)L1623 cardiomyocytes.CONCLUSIONS:
Our data demonstrate the existence in cardiomyocytes of a calcium channel modulatory activity responsive to Ang II generated by the Ang-(1-12)/chymase axis that signals via intracellular receptors. Chronically elevated Ang II in TGR(hAGT)L1623 hearts leading to increased intracellular calcium through ICa-L suggests that activation of this Ang-(1-12)/chymase-governed cardiac intracrine RAS may contribute to the pathological phenotypes observed in the humanized model of chronic hypertension and cardiac hypertrophy.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Angiotensina I
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Angiotensinogênio
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Canais de Cálcio Tipo L
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Miócitos Cardíacos
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Quimases
Limite:
Animals
Idioma:
En
Revista:
Int J Cardiol
Ano de publicação:
2019
Tipo de documento:
Article