APJ acts as a dual receptor in cardiac hypertrophy

Abstract

Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues1. Here we report that genetic loss of APJ confers resistance to chronic pressure overload by dramatically reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechano-sensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and for the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…Recently, however, it has been shown that APJ prompts myocardial hypertrophy in response to mechanical stretch by an apelin-independent, b-arrestin-dependent mechanism. This stretch-mediated hypertrophy is diminished by apelin treatment (Scimia et al 2012). Furthermore, the signalling response induced by stretch is pertussis toxin (PTX)-insensitive and G protein-independent, unlike the response observed with apelin.…”

“…This effect may perhaps be explained by the recent report that APJ signals independently of apelin in response to cardiac mechanical stretch (Scimia et al 2012). APJ KO embryos at E10.5, when lethality begins, have poorly developed vasculature of the yolk sac, delayed formation of the atrioventricular cushion and unusually formed cardinal veins and dorsal aorta (Kang et al 2013).…”

“…Furthermore, the signalling response induced by stretch is pertussis toxin (PTX)-insensitive and G protein-independent, unlike the response observed with apelin. Additionally, stretch diminishes apelin signalling by decreasing G protein activation and increasing b-arrestin recruitment (Scimia et al 2012). Thus, it appears that both apelin and stretch activate APJ to affect cardiac hypertrophy.…”

Biased Signaling Favoring Gi over β-Arrestin Promoted by an Apelin Fragment Lacking the C-terminal Phenylalanine

“…In contrast, K16P, which is biased against ␤-arrestin-dependent signaling, is ineffective, suggesting a direct link between the biased signaling and the differential vasodilatory response promoted by distinct apelin fragments. In addition, Scimia et al (64) have recently shown that a mechanical stretch of cardiomyocytes activates ERK1/2 phosphorylation in an ApelinR-dependent manner, independently of G␣ i activation, and promotes ␤-arrestin recruitment. ERK1/2 activation by ␤-arrestin-dependent signaling pathway leads to a redistribution of ERK1/2 into endosomal vesicles that contain receptor-␤-arrestin complexes as previously shown for AT1a receptor (65).…”

Hubungan Kadar Apelin dengan Disfungsi Diastol pada Penderita Gagal Jantung dengan Fraksi Ejeksi Normal

“…9,10 Apelin meningkat secara bermakna pada kondisi beban tekanan kronik dibanding dengan kondisi normal dan menurun secara bermakna pada disfungsi sistol dengan penurunan yang signifikan terjadi pada jantung yang mengalami fibrosis dan kerusakan otot jantung yang paling berat. 10,11 Penelitian pada binatang yang mengalami hipertensi dan juga beban tekanan yang kronik menyatakan bahwa kadar apelin akan meningkat pada fase awal terjadinya beban tekanan yang tinggi (<12 minggu) dan menjadi normal atau penurunan pada fase selanjutnya (>12 minggu) dengan penurunan yang seiring dengan menurunnya fungsi jantung dan bertambahnya kerusakan pada sel-sel otot jantung.…”