科研之友
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摘要
Angiotensin II (AngII), the main effector peptide of the renin-angiotensin system, plays important roles in cardiovascular regulation in the perinatal period. Despite the well-known stimulatory effect of AngII on vascular contraction, little is known about regulation of contraction of the immature heart by AngII. Here we found that AngII significantly increased the peak amplitude of twitch Ca2+ transients by robustly activating L-type Ca(V)1.2 Ca2+ (Ca(V)1.2) channels in mouse immature but not mature cardiomyocytes. This response to AngII was mediated by AT(1) receptors and -arrestin2. A -arrestin-biased AT(1) receptor agonist was as effective as AngII in activating Ca(V)1.2 channels. Src-family tyrosine kinases (SFKs) and casein kinase 2' (CK2') were sequentially activated when AngII activated Ca(V)1.2 channels. A cyclin-dependent kinase inhibitor, p27(Kip1) (p27), inhibited CK2', and AngII removed this inhibitory effect through phosphorylating tyrosine 88 of p27 via SFKs in cardiomyocytes. In a human embryonic kidney cell line, tsA201 cells, overexpression of CK2' but not c-Src directly activated recombinant Ca(V)1.2 channels composed of C-terminally truncated (1C), the distal C-terminus of (1C), (2C) and (21) subunits, by phosphorylating threonine 1704 located at the interface between the proximal and the distal C-terminus of Ca(V)1.2(1C) subunits. Co-immunoprecipitation revealed that Ca(V)1.2 channels, CK2' and p27 formed a macromolecular complex. Therefore, stimulation of AT(1) receptors by AngII activates Ca(V)1.2 channels through -arrestin2 and CK2', thereby probably exerting a positive inotropic effect in the immature heart. Our results also indicated that -arrestin-biased AT(1) receptor agonists may be used as valuable therapeutics for paediatric heart failure in the future.
- 出版日期2017-7-1
