The effect of angiotensin II on mitogen-activated protein kinase in human cardiomyocytes.
The role of angiotensin II (Ang II)-receptors on mitogen-activated protein kinase (MAPK) activation in cardiomyocytes remains controversial. Therefore, the current study was designed to investigate the actions of AT(1)- and AT(2)-receptors on Ang II-induced extracellular signal-regulated kinase (ERK), p38 and the c-Jun N-terminal kinase (JNK) MAPK activities in human cardiomyocytes. Human cardiac tissue was obtained from open-heart surgery (n=6). The cardiac tissue was minced and incubated in the special tissue culture system for 24 hours in the absence or presence of Ang II (10(-7) M). These studies were repeated with the AT(1)-receptor antagonist losartan (10(-6) M) or the AT(2)-receptor antagonist PD-123319 (10(-6) M). Immunohistochemical staining and Western blot analysis with phospho-antibodies were performed to determine ERK, JNK and p38 activities. Ang II increased ERK and p38 activities in human cardiomyocytes. The effects of Ang II were abolished by losartan and enhanced by PD-123319. Co-incubation with both losartan and PD-123319 resulted in a decrease of ERK and p38 activities in cardiomyocytes. The immunohistochemical staining of JNK showed no significant differences between Ang II alone, Ang II plus losartan and Ang II plus PD-123319 groups. In conclusion, Ang II has a potent effect on ERK and p38 MAPK activities in cardiomyocytes, by acting through AT(1)-receptors. This effect of Ang II is modified by AT(2)-receptors. Therefore, Ang II, via AT(1)- and AT(2)-receptor stimulation, has a distinct effect on MAPK activity in cardiomyocytes.
Wei
C
C
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. cwei@smail.umaryland.edu
Cardarelli
M G
MG
Downing
S W
SW
McLaughlin
J S
JS
D000368:Aged; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D046508:Culture Techniques; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D019808:Losartan / Q000494:pharmacology; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D048051:p38 Mitogen-Activated Protein Kinases
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; C073402:PD 123319; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019808:Losartan