Role of homocysteine and folic acid on the altered calcium homeostasis of platelets from rats with biliary cirrhosis.
Previously, we have found that intracellular calcium homeostasis is altered in platelets from an experimental model of liver cirrhosis, the bile-duct ligated (BDL) rat; these alterations are compatible with the existence of a hypercoagulable state. Different studies indicate that cholestatic diseases are associated with hyperhomocysteinemia; thus, we hypothetized that it could contribute to those platelet alterations. In the present study, we have investigated the role of homocysteine (HCY) in platelet aggregation and calcium signaling in the BDL model. The effect of chronic folic acid treatment was also analyzed. Acute treatment with HCY increased the aggregation response to ADP and calcium responses to thrombin in platelets of control and BDL rats. Capacitative calcium entry was not altered by HCY. Chronic treatment with folic acid decreased platelet aggregation in control and BDL rats, but this decrease was greater in BDL rats. In folic acid-treated rats, thrombin-induced calcium entry and release were decreased in platelet of control rats but unaltered in BDL rats; however, capacitative calcium entry was decreased in platelets of control and BDL rats treated with folic acid. Reactive oxygen species were produced at higher levels by BDL platelets after stimulation with HCY or thrombin and folic acid normalized these responses. HCY plays a role in the enhanced platelet aggregation response of BDL rats, probably through an enhanced formation of ROS. Folic acid pretreatment normalizes many of the platelet alterations shown by BDL rats.
a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain.
Paola
P
Romecín
a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain.
Noemí M
NM
Atucha
a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain.
Esther G
EG
Navarro
a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain.
M Clara
MC
Ortiz
a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain.
David
D
Iyú
b Depto. Fisiología, Fac. Veterinaria , Universidad de Extremadura , Cáceres, Spain.
Juan Antonio
http://orcid.org/0000-0002-9749-2325
JA
Rosado
a Depto. Fisiología, Fac. Medicina, Instituto Murciano de Investigación Biosanitaria (IMIB) , Universidad de Murcia, Murcia, Spain.
Joaquín
http://orcid.org/0000-0002-7243-0240
J
García-Estañ
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002779:Cholestasis / Q000097:blood* / Q000473:pathology; D004195:Disease Models, Animal; D005492:Folic Acid / Q000494:pharmacology*; D006710:Homocysteine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008026:Ligation; D008105:Liver Cirrhosis, Biliary / Q000097:blood* / Q000473:pathology; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
D017382:Reactive Oxygen Species; D006710:Homocysteine; D000244:Adenosine Diphosphate; D005492:Folic Acid; D013917:Thrombin; D002118:Calcium
Bile-duct ligation; calcium signaling; capacitative Ca2+ entry; cholestasis; fura-2; liver cirrhosis; thapsigargin; thrombin