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Carbonic Anhydrase Activation Is Associated With Worsened Pathological Remodeling in Human Ischemic Diabetic Cardiomyopathy

Research output: Contribution to journalArticle

Daniele Torella, Georgina M. Ellison, Michele Torella, Carla Vicinanza, Iolanda Aquila, Claudio Iaconetti, Mariangela Scalise, Fabiola Marino, Beverley J Henning, Fiona C. Lewis, Clarice Gareri, Nadia Lascar, Giovanni Cuda, Teresa Salvatore, Gianantonio Nappi, Ciro Indolfi, Roberto Torella, Domenico Cozzolino, Ferdinando Carlo Sasso

Original languageEnglish
Article numbere000434
Number of pages16
JournalJournal of the American Heart Association
Issue number2
Early online date26 Mar 2014
Accepted/In press24 Dec 2013
E-pub ahead of print26 Mar 2014

King's Authors


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.

Methods and 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 mu m(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.

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