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

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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.

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.

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Most cited references 37

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Myocardial cell death in human diabetes.

A Frustaci, P Anversa, J Kajstura … (2000)

The renin-angiotensin system is upregulated with diabetes, and this may contribute to the development of a dilated myopathy. Angiotensin II (Ang II) locally may lead to oxidative damage, activating cardiac cell death. Moreover, diabetes and hypertension could synergistically impair myocardial structure and function. Therefore, apoptosis and necrosis were measured in ventricular myocardial biopsies obtained from diabetic and diabetic-hypertensive patients. Accumulation of a marker of oxidative stress, nitrotyrosine, and Ang II labeling were evaluated quantitatively. The diabetic heart showed cardiac hypertrophy, cavitary dilation, and depressed ventricular performance. These alterations were more severe with diabetes and hypertension. Diabetes was characterized by an 85-fold, 61-fold, and 26-fold increase in apoptosis of myocytes, endothelial cells, and fibroblasts, respectively. Apoptosis in cardiac cells did not increase additionally with diabetes and hypertension. Diabetes increased necrosis by 4-fold in myocytes, 9-fold in endothelial cells, and 6-fold in fibroblasts. However, diabetes and hypertension increased necrosis by 7-fold in myocytes and 18-fold in endothelial cells. Similarly, Ang II labeling in myocytes and endothelial cells increased more with diabetes and hypertension than with diabetes alone. Nitrotyrosine localization in cardiac cells followed a comparable pattern. In spite of the difference in the number of nitrotyrosine-positive cells with diabetes and with diabetes and hypertension, apoptosis and necrosis of myocytes, endothelial cells, and fibroblasts were detected only in cells containing this modified amino acid. In conclusion, local increases in Ang II with diabetes and with diabetes and hypertension may enhance oxidative damage, activating cardiac cell apoptosis and necrosis.

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Oxidative stress and redox signalling in cardiac hypertrophy and heart failure.

R Looi, Ami A Shah, John Seddon (2007)

Substantial evidence suggests the involvement of oxidative stress in the pathophysiology of congestive heart failure and its antecedent conditions such as cardiac hypertrophy and adverse remodelling after MI. Oxidative stress describes an imbalance between antioxidant defences and the production of reactive oxygen species (ROS), which at high levels cause cell damage but at lower levels induce subtle changes in intracellular signalling pathways (termed redox signalling). ROS are derived from many sources including mitochondria, xanthine oxidase, uncoupled nitric oxide synthases and NADPH oxidases. The latter enzymes are especially important in redox signalling, being implicated in the pathophysiology of hypertension and atherosclerosis, and activated by diverse pathologically relevant stimuli. We review the contribution of ROS to heart failure pathophysiology and discuss potential therapies that may specifically target detrimental redox signalling. Indeed, drugs such as ACE inhibitors and statins may act in part through such mechanisms. A better understanding of redox signalling mechanisms may enable the development of new targeted therapeutic strategies rather than the non-specific antioxidant approaches that have to date been disappointing in clinical trials.

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Author and article information

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (hwp): ahaoa

Journal ID (publisher-id): jah3

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: Blackwell Publishing Ltd

ISSN (Electronic): 2047-9980

Publication date Collection: April 2014

Publication date (Electronic): 25 April 2014

Volume: 3

Issue: 2

Electronic Location Identifier: e000434

Affiliations

[1 ]Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy (D.T., G.M.E., C.V., I.A., C.I., M.S., F.M., C.G., C.I.)

[2 ]Stem Cell and Regenerative Biology Unit (BioStem), Faculty of Sciences, Liverpool John Moores University, Liverpool, UK (D.T., C.V., B.J.H.)

[3 ]Centre of Human and Aerospace Physiological Sciences & Centre for Stem Cells and Regenerative Medicine, King's College London, School of Biomedical Sciences, Guys campus, London, SE1 1UL, UK (G.M.E., F.C.L.)

[4 ]Department of Cardio‐Thoracic and Respiratory Sciences, Second University of Naples, Naples, Italy (M.T., G.N.)

[5 ]Unit of Internal Medicine, Department of Internal and Experimental Medicine ‘Lanzara‐Magrassi’, Second University of Naples, Naples, Italy (N.L., T.S., R.T., D.C., F.C.S.)

[6 ]Center of Cardiovascular Excellence, Second University of Naples, Naples, Italy (N.L., T.S., R.T., D.C., F.C.S.)

[7 ]Laboratory of Proteomics and Mass Spectrometry, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy (G.C.)

Author notes

Correspondence to:Daniele Torella, MD, PhD, Molecular And Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Campus S. Venuta, Viale Europa, Germaneto, 88100 Catanzaro, Italy. E‐mail: dtorella@ 123456unicz.it Ferdinando Carlo Sasso, MD, PhD, Division of Internal Medicine, Department of Internal and Experimental Medicine, Second University of Naples, 80121 Naples, Italy. E‐mail: ferdinando.sasso@ 123456unina2.it

D. Torella, G.M. Ellison, and M. Torella contributed equally to this study.

Article

Publisher ID: jah3435

DOI: 10.1161/JAHA.113.000434

PMC ID: 4187518

PubMed ID: 24670789

SO-VID: f6e28f35-82bd-4fc0-ac95-7f01a930af01

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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

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Abstract

Background

Methods and Results

Conclusions

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Cardiovascular Innovations and Applications

Most cited references 37

Revisiting the principles of microRNA target recognition and mode of action.

Myocardial cell death in human diabetes.

Oxidative stress and redox signalling in cardiac hypertrophy and heart failure.

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