TIMP3 Deficiency Exacerbates Iron Overload-Mediated Cardiomyopathy and Liver Disease: A Key Role of the Iron-overloaded Matrix

Significance

The high morbidity and mortality rate of patients with genetic hemochromatosis and secondary iron overload have been attributed to increased gut absorption of iron and frequent use of blood transfusions, respectively. Iron overload is associated with loss-of-function mutations that disrupt the normal expression of hepcidin or hemojuvelin genes. This results in impaired iron metabolism and excessive accumulation of iron in various organs. Some of the major complications of chronic iron overload include cirrhosis, liver fibrosis, hepatocellular carcinoma, and heart failure. Although some research studies have used murine models to recapitulate the major elements of liver disease and iron overload-induced cardiomyopathy, these models failed to reproduce the processes required to recapitulate the specific symptoms of iron-overload in humans. Moreover, the fact that Tissue Inhibitor of Metalloproteinase 3 (TIMP3) is a dual regulator of extracellular matrix (ECM) remodeling and tissue fibrosis, inflammation, and repair suggests that it may play a role in the occurrence of tissue injuries mediated by iron overload. Thus, this study aimed to investigate the role of TIMP3 in the exacerbation of iron overload-mediated cardiomyopathy and liver disease in mice, using male mice lacking Timp3 (Timp3-/-) and Wild-type (WT) mice.

Scientists at the University of Alberta led by Dr. Gavin Oudit demonstrated a critical l role of TIMP3 in the exacerbation of tissue injuries caused by chronic iron overload. Their research work now published in the American Journal of Physiology-Heart and Circulatory Physiology.

The research team observed that there were no iron deposits in the heart and liver of the placebo group. They also observed that equivalent iron overload and ferroportin protein levels were detected in Timp3-/- and WT hearts. However, lower levels of ferroportin protein and higher levels of iron and hepcidin were detected in Timp3-/- livers compared with WT livers. These findings were in line with the greater hepatomegaly observed in Timp3-/- group compared with the WT group. The authors also observed that the expression of ferroportin remained unaltered in the WT heart and increased in the Timp3-/- heart while the expression of hepcidin remained unaltered in the Timp3-/- heart and increased in the WT heart. However, the expression levels of ferroportin and hepcidin in the liver of both iron-injected groups was high compared with the placebo group.

In addition, their study identified a systolic dysfunction in Timp3-/- heart and a diastolic dysfunction in both Timp3-/- and WT heart. Also, an increase in left atrial dimensions, invasive measurement of cardiac function and Nppa expression was confirmed in the Timp3-/- heart. Also observed were aberrant and increased myocardial fibrosis, upregulation of the myocardial MMP axis and increased expression of proinflammatory cytokines in Timp3-/- heart compared with WT heart. However, the infiltration of neutrophils and macrophages in Timp3-/- heart was not detected.

Furthermore, it was found that the loss of TIMP3 increased the infiltration of macrophages and neutrophils, hepatic inflammatory response (IL-1β and monocyte chemoattractant protein-1), hepatic fibrotic response and MMP expression (MMP-12 and MMP-13) in Timp3-/- liver compared with WT liver. However, equivalent levels of MMP-2 and MMP-9 expression was detected in both Timp3-/- and WT liver.

Indeed Pavel Zhabyeyev and colleagues identified a novel role of TIMP3 in the prevention of iron-mediated cardiomyopathy and liver disease. Their findings will advance subsequent research studies on the role of TIMP3 in the control of the ECM, inflammation, and contractility iron-mediated pathology as well as ways to use this protective molecule to reduce iron-mediated tissue injury.

Reference

Zhabyeyev, P., Das, S.K., Basu, R., Shen, M., Patel, V.B., Kassiri, Z., and Oudit, G.Y. TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease, American Journal of Physiology-Heart and Circulatory Physiology (2018) 314, H978–H990.

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