Angiotensin II receptors subtypes mediate diverse gene expression profile in adult hypertrophic cardiomyocytes.
1. Although the systemic and cardiac renin-angiotensin systems are known to be activated in the setting of pressure overload, the actions and signaling mechanisms of angiotensin (Ang) II via AT(1) and AT(2) receptors in hypertrophic cardiomyocytes (CM) remain largely unclear. 2. Hypertrophic CM were prepared from rats with aortic banding for 8 weeks, cultured and then treated as follows: (i) 1 micromol/L AngII for 24 h; (ii) 10 micromol/L losartan (an AT(1) receptor antagonist) for 1 h followed by 1 micromol/L AngII for 24 h; and (iii) 10 micromol/L PD123319 (an AT(2) receptor antagonist) for 1 h followed by 1 micromol/L AngII for 24 h. Changes in the expression of genes following stimulation of AT(1) and AT(2) receptors specific to G-protein-coupled receptor (GPCR) signaling pathways were tested using GEArray (Superarray, Bethesda, MD, USA). The effects of AngII, acting via AT(1) and AT(2) receptors, on the expression of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 were confirmed by reverse transcription-polymerase chain reaction and radioimmunoassay. 3. The genes regulated via stimulation of AT(1) receptors were mainly restricted to the signaling pathways including cAMP/protein kinase (PK) A, Ca(2+), PKC, protein tyrosine kinase, mitogen-activated protein kinases, phosphatidylinositol 3-kinase and nuclear factor-kappaB. In addition to these pathways related to activation of AT(1) receptors, four additional signaling pathways were found to be associated with stimulation of AT(2) receptors, including phospholipase C, nitric oxide/cGMP, Rho and Janus kinase/signal transducer and activator of transcription. Blockade of AT(2) receptors decreased the mRNA and protein expression of TNF-alpha and IL-1beta, whereas blockade of AT(1) receptors had no such effect. 4. In conclusion, in hypertrophic CM, AngII leads to distinct signaling responses mediated by AT(1) and AT(2) receptors. Stimulation of AT(2) receptors appears to have a greater influence on GPCR-signaling than stimulation of AT(1) receptors. Angiotensin II enhances the synthesis and secretion of TNF-alpha and IL-1beta in hypertrophic CM, which is mediated by AT(2), but not AT(1), receptors.
Zhou
Juan
J
Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Xu
Xin
X
Liu
Jin-Jun
JJ
Lin
Yuan-Xi
YX
Gao
Guang-Dao
GD
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D019808:Losartan / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan