Suppression of cardiac phosphatidate phosphohydrolase 1 activity and lipin mRNA expression in Zucker diabetic fatty rats and humans with type 2 diabetes mellitus.
Lipin functions in mammalian phospholipid biosynthesis through its phosphatidate phosphohydrolase 1 (PAP(1)) activity. Here, we studied cardiac PAP(1) activity and lipin expression ex vivo in 8-month-old Zucker diabetic fatty (ZDF) rats and humans with type 2 diabetes mellitus undergoing open heart surgery for coronary bypass grafting. Compared to non-diabetic littermates (ZDF-fa/+), left ventricular PAP(1) activity was 29% lower in diabetic ZDF-fa/fa rats. Left ventricular PAP(1) activities were 2.1-fold (ZDF-fa/fa) and 3.6-fold (ZDF-fa/+) higher than the respective atrial activities, indicating marked differences in cardiac distribution of PAP(1). PAP(1) activity was highly related with cardiac lipin-1 and lipin-3 mRNA expression in ZDF rats (r=0.99 and 0.96). Consistent with the findings in experimental animals, human atrial tissue displayed PAP(1) activity that was 33% lower in those having diabetes than in non-diabetic controls. Accordingly, atrial lipin-1 and lipin-3 mRNA expression in diabetic patients was 50% and 59% lower as in non-diabetic patients, respectively. Insulin therapy increased both PAP(1) activity and lipin mRNA expression in diabetic patients. We conclude that suppression of cardiac PAP(1) activity/lipin expression may contribute to metabolic dysfunction of the diabetic heart.
Burgdorf
Christof
C
Department of Internal Medicine II, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany. christof.burgdorf@uk-sh.de
Hänsel
Laura
L
Heidbreder
Marc
M
Jöhren
Olaf
O
Schütte
Frank
F
Schunkert
Heribert
H
Kurz
Thomas
T
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy; D006325:Heart Atria / Q000201:enzymology / Q000378:metabolism; D006352:Heart Ventricles / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D000073718:Pancreatitis-Associated Proteins; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker
D007328:Insulin; C502575:LPIN2 protein, human; C530902:Lpin1 protein, rat; D009687:Nuclear Proteins; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D012333:RNA, Messenger; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase