Highlights
- •Ang-(1–12) as a chymase-dependent substrate for generating Ang II inotropic activity
- •Ang-(1–12) stimulates myocyte contractile function and [Ca2+]iT in both normal and HF.
- •HF reduces Ang-(1–12) actions on myocyte contractility and [Ca2+]i regulation.
- •Altered Ang-(1–12) response in HF is mediated through a cAMP-dependent mechanism.
- •Attenuated cardiac effect of Ang-(1–12) in HF is coupled to both Gs and Gi proteins.
Abstract
Background
Angiotensin-(1–12) [Ang-(1–12)] is a chymase-dependent source for angiotensin II (Ang
II) cardiac activity. The direct contractile effects of Ang-(1–12) in normal and heart
failure (HF) remain to be demonstrated. We assessed the hypothesis that Ang-(1–12)
may modulate [Ca2+]i regulation and alter cardiomyocyte contractility in normal and HF rats.
Methods and results
We compared left ventricle (LV) myocyte contractile and calcium transient ([Ca2+]iT) responses to angiotensin peptides in 16 SD rats with isoproterenol-induced HF and
16 age-matched controls. In normal myocytes, versus baseline, Ang II (10−6 M) superfusion significantly increased myocyte contractility (dL/dtmax: 40%) and [Ca2+]iT (29%). Ang-(1–12) (4 × 10−6 M) caused similar increases in dL/dtmax (34%) and [Ca2+]iT (25%). Compared with normal myocytes, superfusion of Ang II and Ang-(1–12) in myocytes
obtained from rats with isoproterenol-induced HF caused similar but significantly
attenuated positive inotropic actions with about 42% to 50% less increases in dL/dtmax and [Ca2+]iT. Chymostatin abolished Ang-(1–12)-mediated effects in normal and HF myocytes. The
presence of an inhibitory cAMP analog, Rp-cAMPS prevented Ang-(1–12)-induced inotropic
effects in both normal and HF myocytes. Incubation of HF myocytes with pertussis toxin
(PTX) further augmented Ang II-mediated contractility.
Conclusions
Ang-(1–12) stimulates cardiomyocyte contractile function and [Ca2+]iT in both normal and HF rats through a chymase mediated action. Altered inotropic responses
to Ang-(1–12) and Ang II in HF myocytes are mediated through a cAMP-dependent mechanism
that is coupled to both stimulatory G and inhibitory PTX-sensitive G proteins.
Keywords
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Article info
Publication history
Published online: April 20, 2018
Accepted:
March 13,
2018
Received in revised form:
February 23,
2018
Received:
January 19,
2018
Footnotes
☆Grant Support: This study was supported by the National Institutes of Health grants [R01AG049770 (HJ Cheng); P01HL051952-21 (CM Ferrario); R01HL074318 (CP Cheng)] and National Natural Science Foundation of China (81270252) (WM Li).
☆☆All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and the discussed interpretation.
★Abstract presented at the American Heart Association Meeting.
Identification
Copyright
© 2018 Elsevier B.V. All rights reserved.
