Open AccessCarbonic Anhydrase Activation Is Associated With Worsened Pathological Remodeling in Human Ischemic Diabetic Cardiomyopathy
Author(s) -
Torella Daniele,
Ellison Georgina M.,
Torella Michele,
Vicinanza Carla,
Aquila Iolanda,
Iaconetti Claudio,
Scalise Mariangela,
Marino Fabiola,
Henning Beverley J.,
Lewis Fiona C.,
Gareri Clarice,
Lascar Nadia,
Cuda Giovanni,
Salvatore Teresa,
Nappi Gianantonio,
Indolfi Ciro,
Torella Roberto,
Cozzolino Domenico,
Sasso Ferdinando Carlo
Publication year - 2014
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000434
Subject(s) - medicine , diabetic cardiomyopathy , sodium–hydrogen antiporter , heart failure , cardiology , myocyte , endocrinology , myocardial infarction , downregulation and upregulation , muscle hypertrophy , cardiomyopathy , diabetes mellitus , sodium , biochemistry , biology , chemistry , organic chemistry , gene
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 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 micro RNA ‐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.