Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis

Abstract

Cardiac damage associated with iron overload is the most common cause of morbidity and mortality in patients with hereditary hemochromatosis, but the precise mechanisms leading to disease progression are largely unexplored. Here we investigated the effects of iron overload and age on cardiac hypertrophy using 1-, 5- and 12-month old Hfe-deficient mice, an animal model of hemochromatosis in humans. Cardiac iron levels increased progressively with age, which was exacerbated in Hfe-deficient mice. The heart/body weight ratios were greater in Hfe-deficient mice at 5- and 12-month old, compared with their age-matched wild-type controls. Cardiac hypertrophy in 12-month old Hfe-deficient mice was consistent with decreased alpha myosin and increased beta myosin heavy chains, suggesting an alpha-to-beta conversion with age. This was accompanied by cardiac fibrosis and up-regulation of NFAT-c2, reflecting increased calcineurin/NFAT signaling in myocyte hypertrophy. Moreover, there was an age-dependent increase in the cardiac isoprostane levels in Hfe-deficient mice, indicating elevated oxidative stress. Also, rats fed high-iron diet demonstrated increased heart-to-body weight ratios, alpha myosin heavy chain and cardiac isoprostane levels, suggesting that iron overload promotes oxidative stress and cardiac hypertrophy. Our findings provide a molecular basis for the progression of age-dependent cardiac stress exacerbated by iron overload hemochromatosis.

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

“…By reducing intracellular iron levels, cardiomyocytes protect from iron overload-induced oxidative stress. In patients with hereditary hemochromatosis and patients with β-thalassemia, iron overload exacerbated cardiac hypertrophy 8,39 . Intracellular ferrous iron-also called labile iron-is readily oxidized by the Haber-Weiss reaction, resulting in cellular ROS formation 40 ; in the hearts of older rats, ferritin levels are increased, possibly as a protective response to oxidative stress from ROS accumulation 36,41 .…”

Protection and Safety Evaluation of Live Constructions Derived from the Pgm− and pPCP1− Yersinia pestis Strain

“…The attenuated Y. pestis Pgm − strain was lethal to an individual with hereditary hemochromatosis manifesting iron overload in tissues [11]. The Hfe −/− mice display the iron overload phenotype that was similarly observed in humans with hereditary hemochromatosis [36,39]. Therefore, we used Hfe −/− mice to further evaluate safety profiles of KIM10(pCD1Ap) and YPS19(pCD1Ap) strains by i.m.…”

The Case for an Estrogen-iron Axis in Health and Disease

“…2), which may partially explain the paradoxical outcomes of HRT in postmenopausal women. Iron overload in postmenopausal women has been shown to increase the risk of hot flashes [51], osteoporosis [52], metabolic syndrome [53], cardiac hypertrophy and cardiovascular complications [54,55] and brain aging and neurodegenerative disorders [56] among others. Both iron and E2 have been separately implicated in diseases, but whether an E2-iron axis is at play has never been considered.…”

“…The progressive decline of endogenous E2 levels during menopause is a risk factor for heart disease [54,55], hence the use of HRT to lower the risk of heart disease in postmenopausal women [74][75][76]. However, well-designed studies have indicated that HRT does not lower the risk of heart disease in postmenopausal women [55,77,78].…”