Cross-talk between inflammation and angiotensin II: studies based on direct transfection of cardiomyocytes with AT1R and AT2R cDNA.
Ischemic myocardium exhibits inflammation, local angiotensin II (Ang II) generation and up-regulation of LOX-1, a lectin-like ox-LDL receptor. To define the inter-active roles of Ang II and inflammation in furthering tissue injury, cultured HL-1 cardiomyocytes were treated with Ang II. Ang II treatment up-regulated the expression of Ang II type 1 (AT1R) and type 2 (AT2R) receptors as well as LOX-1. Ang II also activated p44/42MAPK, p38MAPK, c-Jun and NF-κB, and increased the expression of inflammation-related genes (interleukins-6, interleukins-10, tumor necrosis factor-α, intercellular adhesion molecule-1). To study how inflammation per se might affect expression of Ang II receptors and LOX-1, cultured, cardiomyocytes were treated with lipopolysaccharide (LPS). Like Ang II, LPS increased the expression of AT1R, AT2R and LOX-1. LPS also activated mitogen-acticated protein kinase (MAPKs), c-Jun and NF-κB, and pro-inflammatory genes. The selective inhibitors of MAPKs, c-Jun and NF-κB each blocked the transcription of LOX-1 and pro-inflammatory genes in response to Ang II as well as LPS. These observations suggested a positive feedback between Ang II and inflammation. To delineate the role of AT1R and AT2R in LOX-1 expression, another set of cardiomyocytes were transfected with AT1R or AT2R cDNA. Forced over-expression of AT1R resulted in activation of MAPKs, c-Jun and NF-κB, up-regulation of inflammatory genes and LOX-1; on the other hand forced AT2R over-expression induced up-regulation of pro-apoptotic signals (pro-IL-1β and IL-1β), and decreased LOX-1 expression. These studies show that both Ang II and inflammation mediator LPS up-regulate AT1R, AT2R and LOX-1 expression. Up-regulation of AT1R promotes inflammation and LOX-1 expression, whereas up-regulation of AT2R promotes apoptosis signals and decreases LOX-1 expression.
Central Arkansas Veterans Healthcare System, Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205,  USA.
Xianwei
X
Wang
Magomed
M
Khaidakov
Zufeng
Z
Ding
Sona
S
Mitra
Jingjun
J
Lu
Shijie
S
Liu
Jawahar L
JL
Mehta
D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis* / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis* / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation
D016207:Cytokines; D018076:DNA, Complementary; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495138:Olr1 protein, mouse; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D051127:Scavenger Receptors, Class E; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases