Cardiomyopathy and heart failure are potentially fatal complications of diabetes. They also represent a growing public health problem due to the worldwide obesity epidemic, unhealthy nutrition and associated increase in the number of patients with diabetes. However, the molecular mechanisms leading to diabetes-induced cardiomyocyte injury are still not fully understood making the development of protective therapies very difficult. Recently, we found that the redox regulator, thioredoxin-interacting protein (TXNIP) is induced by glucose, that TXNIP overexpression enhances apoptosis and that cardiac TXNIP expression is upregulated in diabetes, suggesting that increased expression of TXNIP may play a role in diabetic cardiomyocyte injury. TXNIP was also found to be increased in cardiomyocytes after myocardial infarction and knock down of TXNIP reduced the associated apoptosis and fibrosis. Surprisingly, we observed that calcium channel blocker lower cardiac expression of TXNIP, as well as of cleaved caspase-3 and collagen in normal mice. The hypothesis is therefore that decreasing TXNIP expression may represent a novel strategy to inhibit diabetes-induced cardiomyocyte damage.
The aims are:
SPECIFIC AIM 1. Study the effects of calcium channel blocker on diabetes-induced TXNIP expression and apoptosis in heart and elucidate the molecular mechanisms involved. Wild-type mice will be made diabetic by streptozotocin (STZ) injection and the effects of calcium channel blocker on cardiac apoptosis, fibrosis and the expression of TXNIP, cleaved caspase-3 and collagen will be assessed by TUNEL, histochemistry and immuoblotting. Effects on cardiac function will be analyzed by echocardiography. To assess the molecular mechanisms by which calcium channel blocker regulate TXNIP transcription, a detailed promoter analysis will be performed using H9C2 cardiomyocytes.
SPECIFIC AIM 2. Assess whether TXNIP-deficient mice are protected against diabetes-induced cardiac alterations. These studies will be facilitated by the availability of a unique mouse model (HcB-19) harboring a natural nonsense mutation in the TXNIP gene. TXNIP-mutant HcB-19 mice will be rendered diabetic with STZ and the effects of TXNIP-deficiency on cardiomyocyte apoptosis, fibrosis and function analyzed as under aim 1. The results of these studies should help define the role of TXNIP in diabetes-induced cardiomyocyte damage, provide insight into the mechanisms involved, and reveal potential treatment strategies directed towards enhancing cardiomyocyte survival and preventing cardiomyopathy and heart failure. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Ershow, Abby
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University of Wisconsin Madison
Internal Medicine/Medicine
Schools of Medicine
United States
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Cha-Molstad, Hyunjoo; Xu, Guanlan; Chen, Junqin et al. (2012) Calcium channel blockers act through nuclear factor Y to control transcription of key cardiac genes. Mol Pharmacol 82:541-9
Saxena, Geetu; Chen, Junqin; Shalev, Anath (2010) Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein. J Biol Chem 285:3997-4005
Chen, Junqin; Fontes, Ghislaine; Saxena, Geetu et al. (2010) Lack of TXNIP protects against mitochondria-mediated apoptosis but not against fatty acid-induced ER stress-mediated beta-cell death. Diabetes 59:440-7
Cha-Molstad, Hyunjoo; Saxena, Geetu; Chen, Junqin et al. (2009) Glucose-stimulated expression of Txnip is mediated by carbohydrate response element-binding protein, p300, and histone H4 acetylation in pancreatic beta cells. J Biol Chem 284:16898-905
Chen, Junqin; Cha-Molstad, Hyunjoo; Szabo, Anna et al. (2009) Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein. Am J Physiol Endocrinol Metab 296:E1133-9