Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy

J Am Heart Assoc. 2014 Mar 26;3(2):e000434. doi: 10.1161/JAHA.113.000434.


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 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.

Keywords: apoptosis; carbonic anhydrase; diabetes mellitus; hypertrophy; microRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apoptosis
  • Blood Glucose / metabolism
  • Carbonic Anhydrase I / genetics
  • Carbonic Anhydrase I / metabolism*
  • Carbonic Anhydrase II / genetics
  • Carbonic Anhydrase II / metabolism*
  • Cardiomegaly / enzymology
  • Cardiomegaly / pathology
  • Cation Transport Proteins / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Cardiomyopathies / enzymology*
  • Diabetic Cardiomyopathies / pathology
  • Diabetic Cardiomyopathies / physiopathology
  • Endothelial Cells / enzymology*
  • Endothelial Cells / pathology
  • Enzyme Activation
  • Female
  • Humans
  • Male
  • MicroRNAs / metabolism
  • Middle Aged
  • Myocardial Ischemia / enzymology*
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / physiopathology
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Phosphorylation
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers / metabolism
  • Up-Regulation
  • Ventricular Remodeling*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Blood Glucose
  • Cation Transport Proteins
  • MIRN23a microRNA, human
  • MicroRNAs
  • SLC9A1 protein, human
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • p38 Mitogen-Activated Protein Kinases
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II