Abstract 14651: Cardiac Overexpression of Delta-aminolevulinic Acid Synthase 2 (ALAS2) Leads to Exaggerated Response to Ischemic Injury Through an Increase in Heme Production
Introduction: Cardiac dysfunction is a key feature of iron overload diseases, such as hereditary hemochromatosis and Friedrich’s ataxia. Excess iron leads to the overproduction of reactive oxygen species (ROS), which can have detrimental effects on the heart. Mitochondria play an important role in the regulation of cellular iron availability through the synthesis of heme, which begins in the mitochondria by the rate-limiting enzyme delta-aminolevulinic acid synthase (ALAS). We recently showed that heme and ALAS2 levels are increased in the hearts of patients with heart failure, but it is unknown whether this increase in ALAS2 is a causative or consequential factor in heart failure. We hypothesized that cardiac-specific ALAS2 overexpression renders the heart more susceptible to the development of heart failure, and that the detrimental effects of ALAS2 on the heart are through increases in heme and oxidative stress.
Results: Although transgenic (TG) mice overexpressing ALAS2 in the heart exhibit normal cardiac function at baseline, ejection fraction and fractional shortening were significantly reduced in ALAS2 TG mice compared to non-TG control mice after coronary ligation. Heart and lung weight were also significantly increased in ALAS2 TG mice that underwent coronary ligation compared to non-TG control mice, consistent with exacerbated heart failure. In H9c2 cardiac myoblasts, ALAS2 expression and heme levels were positively regulated by hypoxia and erythropoietin (EPO), two pathways that are frequently altered in failing hearts. Suppression of ALAS2 upregulation by EPO or hypoxia using siRNA reversed the increase in heme, suggesting that upregulation of ALAS2 in heart failure may be responsible for the increase in heme levels. Finally, ALAS2 overexpression or exogenous heme administration led to an increase in mitochondrial ROS and cell death, suggesting that elevated ALAS2 and heme production in heart failure may be maladaptive through increased oxidative stress.
Conclusions: We show that mice with cardiac-specific overexpression of ALAS2 are more susceptible to heart failure by coronary ligation, and that the detrimental effects of ALAS2 on the heart are through increased production of heme and oxidative stress.
Author Disclosures: K.T. Sawicki: None. R. Wu: None. M. Bayeva: None. H. Chang: None. H. Ardehali: None.
- © 2014 by American Heart Association, Inc.