Diverse regulation of cardiac expression of relaxin receptor by α1- and β1-adrenoceptors.
OBJECTIVE
Relaxin, a new drug for heart failure therapy, exerts its cardiac actions through relaxin family peptide receptor 1 (RXFP1). Factors regulating RXFP1 expression remain unknown. We have investigated effects of activation of adrenoceptors (AR), an important modulator in the development and prognosis of heart failure, on expression of RXFP1 in rat cardiomyocytes and mouse left ventricles (LV).


METHODS
Expression of RXFP1 at mRNA (real-time PCR) and protein levels (immunoblotting) was measured in cardiomyocytes treated with α- and β-AR agonists or antagonists. RXFP1 expression was also determined in the LV of transgenic mouse strains with cardiac-restricted overexpression of α1A-, α1B- or β2-AR. Specific inhibitors were used to explore signal pathways involved in α1-AR mediated regulation of RXFP1 in cardiomyocytes.


RESULTS
In cultured cardiomyocytes, α1-AR stimulation resulted in 2-3 fold increase in RXFP1 mRNA (P < 0.001), which was blocked by specific inhibitors for protein kinase C (PKC) or mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK). Activation of β1-, but not β2-AR, significantly inhibited RXFP1 expression (P < 0.001). Relative to respective wild-type controls, RXFP1 mRNA levels in the LV of mice overexpressing α1A- or α1B-AR were increased by 3- or 10-fold, respectively, but unchanged in β2-AR transgenic hearts. Upregulation by α1-AR stimulation RXFP1 expression was confirmed at protein levels both in vitro and in vivo.


CONCLUSIONS
Expression of RXFP1 was up-regulated by α1-AR but suppressed by β-AR, mainly β1-AR subtype, in cardiomyocytes. Future studies are warranted to characterize the functional significance of such regulation, especially in the setting of heart failure.
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria, 3004, Australia.
Xiao-Lei
XL
Moore
Yidan
Y
Su
Yingli
Y
Fan
You-Yi
YY
Zhang
Elizabeth A
EA
Woodcock
Anthony M
AM
Dart
Xiao-Jun
XJ
Du
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics; D018000:Receptors, Peptide / Q000187:drug effects* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D012333:RNA, Messenger; C478103:RXFP1 protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D018342:Receptors, Adrenergic, beta-1; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C504789:Rxfp1 protein, rat