論文紹介著者

第一著者名・掲載雑誌・号・掲載年月

Maria Cecilia Scimia／Nature (2012) doi:10.1038/nature11263. Published online 18 July 2012

文献の英文表記：著者名・論文の表題・雑誌名・巻・号・ページ・発行年（西暦）

Maria Cecilia Scimia, Cecilia Hurtado, Saugata Ray, Scott Metzler, Ke Wei, Jianming Wang, Chris E. Woods, Nicole H. Purcell, Daniele Catalucci, Takashi Akasaka, Orlando F. Bueno, George P. Vlasuk, Perla Kaliman, Rolf Bodmer, Layton H. Smith, Euan Ashley, Mark Mercola, Joan Heller Brown & Pilar Ruiz-Lozano. APJ acts as a dual receptor in cardiac hypertrophy. Nature (2012) doi:10.1038/nature11263. Published online 18 July 2012

論文解説

Background

1, Cardiac hypertrophy:
Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues.

2, Apelin-APJ system:
Apelin, the endogenous ligand for the G-protein-coupled APJ receptor, is emerging as a key hormone in cardiovascular homoeostasis. It is expressed in a diverse range of tissues with particular preponderance for the cardiovascular system, being found in both the heart and vasculature.

3, Mechanosensor:
mechanosensors are a groups of cell surface receptors which could sense the mechanical stress and lead to activation of signaling pathway and biological effect.

4, GPCRs signaling in the heart disease:
G-protein-coupled receptors (GPCRs) have been widely implicated in the control of cardiac function. These receptors couple to heterotrimeric GTP-binding proteins of the Gαs, Gαi, Gαq/11 and Gα12/13 families, and transduce the GPCR signal to intracellular targets. Numerous studies have linked Gαs to increased contractility, Gαq/11 to pathological hypertrophy and Gαi to cardioprotection. APJ is a GPCR identified as the receptor for the adipokine apelin. Apelin-activated APJ signals through Gαi, exerting a positive effect on cardiac contractility and a vasodilator activity that counteracts angiotensin-II-induced atheroma.

5, Frank-Starling law of the heart:

The Frank-Starling law of the heart states that the stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (the end diastolic volume). The increased volume of blood stretches the ventricular wall, causing cardiac muscle to contract more forcefully (the so-called Frank-Starling mechanisms). The stroke volume may also increase as a result of greater contractility of the cardiac muscle during exercise, independent of the end-diastolic volume.

Results

1, APJ knockout (APJ-KO) mice are protected from pressure overload induced hypertrophy. APJ-KO mice responded to transaortic constriction (TAC) by initially increasing cardiac mass, but the maladaptive progression to dilated ventricular hypertrophy was blunted shortly after injury. The protective effect persisted long-term in all parameters measured, including diminished cardiomyocyte size, reduced fibrosis, sustained cardiac contractility relative to WT.

2, Apelin modulated the response to stretch only in cardiomyocytes with APJ receptors. Freshly isolated adult cardiomyocytes from WT mice showed a significantly higher frank-starling gain (FSG) than cardiomyocytes from APJ-KO mice. Treatment with apelin decreased the FSG in WT cardiomyocytes but showed no effect in APJ-KO cells. Therefore, apelin modulated the response to stretch only in cardiomyocytes with APJ receptors.

3, Stretch activation of APJ enhances β-arrestin while reducing G-protein signalling.

4, APJ activation through mechanical stretch elicits cardiac hypertrophy.

Conclusion

In summary, the mechano-response of APJ is necessary (blunted hypertrophic response to TAC of APJ-KO mice) and sufficient (stretch induction of ANF expression occurs in cells expressing APJ) to trigger myocardial hypertrophy in a β-arrestin-dependent manner. A beneficial effect will be obtained not by general apelin receptor agonism, but rather by selectively inhibiting the ability of APJ to respond to mechanical stretch or by blocking its interaction with molecules that initiate pathological signalling cascades.