Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT(1) receptors.
Lipopolysaccharide (LPS) from gram-negative bacteria circulates in acute, subacute, and chronic conditions. It was hypothesized that LPS directly induces cardiac apoptosis. In adult rat ventricular myocytes (isolated with depyrogenated digestive enzymes to minimize tolerance), LPS (10 ng/ml) decreased the ratio of Bcl-2 to Bax at 12 h; increased caspase-3 activity at 16 h; and increased annexin V, propidium iodide, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining at 24 h. Apoptosis was blocked by the caspase inhibitor benzyloxycarbonyl-valine-alanine-aspartate fluoromethylketone (Z-VAD-fmk), captopril, and angiotensin II type 1 receptor (AT(1)) inhibitor (losartan), but not by inhibitors of AT(2) receptors (PD-123319), tumor necrosis factor-alpha (TNFRII:Fc), or nitric oxide (N(G)-monomethyl-L-arginine). Angiotensin II (100 nmol/l) induced apoptosis similar to LPS without additive effects. LPS in vivo (1 mg/kg iv) increased apoptosis in left ventricular myocytes for 1-3 days, which dissipated after 1-2 wk. Losartan (23 mg. kg(-1). day(-1) in drinking water for 3 days) blocked LPS-induced in vivo apoptosis. In conclusion, low levels of LPS induce cardiac apoptosis in vitro and in vivo by activating AT(1) receptors in myocytes.
Cardiology Section, Department of Medicine, Veterans Affairs, San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Hai Ling
HL
Li
Jun
J
Suzuki
Evelyn
E
Bayna
Fu-Min
FM
Zhang
Erminia
E
Dalle Molle
Aaron
A
Clark
Robert L
RL
Engler
Wilbur Y W
WY
Lew
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology*; D016276:Ventricular Function / Q000187:drug effects*
D008070:Lipopolysaccharides; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin