Effects of insulin replacements, inhibitors of angiotensin, and PKCbeta's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats.
High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)beta inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and (13)C nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKCbeta or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.
Arikawa
Emi
E
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Ma
Ronald C W
RC
Isshiki
Keiji
K
Luptak
Ivan
I
He
Zhiheng
Z
Yasuda
Yutaka
Y
Maeno
Yasuhiro
Y
Patti
Mary Elizabeth
ME
Weir
Gordon C
GC
Harris
Robert A
RA
Zammit
Victor A
VA
Tian
Rong
R
King
George L
GL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000809:Angiotensins / Q000037:antagonists & inhibitors*; D000818:Animals; D002216:Captopril / Q000627:therapeutic use; D002462:Cell Membrane / Q000201:enzymology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000601:surgery; D004343:Drug Implants; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects; D007328:Insulin / Q000627:therapeutic use*; D016381:Islets of Langerhans Transplantation; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D020411:Oligonucleotide Array Sequence Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D012313:RNA / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D004343:Drug Implants; D007328:Insulin; D047492:Peroxisome Proliferator-Activated Receptors; D012313:RNA; D002216:Captopril; D011493:Protein Kinase C; D064546:Protein Kinase C beta