title: Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy.
abstract: BACKGROUND
  Diabetes mellitus (DM) has multifactorial detrimental effects on myocardial tissue. Recently, carbonic anhydrases (CAs) have been shown to play a major role in diabetic microangiopathy but their role in the diabetic cardiomyopathy is still unknown.
  
  
  RESULTS
  We obtained left ventricular samples from patients with DM type 2 (DM-T2) and nondiabetic (NDM) patients with postinfarct heart failure who were undergoing surgical coronary revascularization. Myocardial levels of CA-I and CA-II were 6- and 11-fold higher, respectively, in DM-T2 versus NDM patients. Elevated CA-I expression was mainly localized in the cardiac interstitium and endothelial cells. CA-I induced by high glucose levels hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro. Accordingly, capillary density was significantly lower in the DM-T2 myocardial samples (mean±SE=2152±146 versus 4545±211/mm(2)). On the other hand, CA-II was mainly upregulated in cardiomyocytes. The latter was associated with sodium-hydrogen exchanger-1 hyperphosphorylation, exaggerated myocyte hypertrophy (cross-sectional area 565±34 versus 412±27 μm(2)), and apoptotic death (830±54 versus 470±34 per 10(6) myocytes) in DM-T2 versus NDM patients. CA-II is activated by high glucose levels and directly induces cardiomyocyte hypertrophy and death in vitro, which are prevented by sodium-hydrogen exchanger-1 inhibition. CA-II was shown to be a direct target for repression by microRNA-23b, which was downregulated in myocardial samples from DM-T2 patients. MicroRNA-23b is regulated by p38 mitogen-activated protein kinase, and it modulates high-glucose CA-II-dependent effects on cardiomyocyte survival in vitro.
  
  
  CONCLUSIONS
  Myocardial CA activation is significantly elevated in human diabetic ischemic cardiomyopathy. These data may open new avenues for targeted treatment of diabetic heart failure.
authors.affiliation: Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Torella
authors.forename: Georgina M
authors.initials: GM
authors.lastname: Ellison
authors.forename: Michele
authors.initials: M
authors.lastname: Torella
authors.forename: Carla
authors.initials: C
authors.lastname: Vicinanza
authors.forename: Iolanda
authors.initials: I
authors.lastname: Aquila
authors.forename: Claudio
authors.initials: C
authors.lastname: Iaconetti
authors.forename: Mariangela
authors.initials: M
authors.lastname: Scalise
authors.forename: Fabiola
authors.initials: F
authors.lastname: Marino
authors.forename: Beverley J
authors.initials: BJ
authors.lastname: Henning
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Lewis
authors.forename: Clarice
authors.initials: C
authors.lastname: Gareri
authors.forename: Nadia
authors.initials: N
authors.lastname: Lascar
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cuda
authors.forename: Teresa
authors.initials: T
authors.lastname: Salvatore
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Nappi
authors.forename: Ciro
authors.initials: C
authors.lastname: Indolfi
authors.forename: Roberto
authors.initials: R
authors.lastname: Torella
authors.forename: Domenico
authors.initials: D
authors.lastname: Cozzolino
authors.forename: Ferdinando Carlo
authors.initials: FC
authors.lastname: Sasso
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D024401:Carbonic Anhydrase I / Q000235:genetics / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology; D027682:Cation Transport Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D058065:Diabetic Cardiomyopathies / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D015854:Up-Regulation; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D027682:Cation Transport Proteins; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D048051:p38 Mitogen-Activated Protein Kinases; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II
keywords: apoptosis; carbonic anhydrase; diabetes mellitus; hypertrophy; microRNA