Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury

Abstract

BackgroundHeme is an essential iron-containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate-limiting enzyme in heme synthesis, δ-aminolevulinic acid synthase 2 (ALAS2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS2) leads to increased oxidative stress and cell death in the heart.Methods and ResultsWe first showed that ALAS2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac-specific overexpression of ALAS2. While ALAS2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to nontransgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death observed with ALAS2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS2-overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to nonischemic cardiomyopathy.ConclusionsHeme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure.

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

“…Data shown as mean ± SEM n = 8 mice in WT and 3 mice in Berk-SS; Mann-Whitney U test; ns, P > 0.05; *P ≤ 0.05. enzyme ALAS2. Recently, increased myocardial ALAS2 expression has been shown to potentiate ischemic injury and to be associated with heart failure (80,81). The finding of ALAS2 up-regulation in SCA is consistent with the myocardial ischemia observed on histopathology and EM.…”

Getting to the “Heart” of Cardiac Disease by Decreasing Mitochondrial Iron

“…In humans, end-stage HF is also associated with increased cardiac mitochondrial heme iron. 7 Taken together, these studies suggest that: 1) mitochondrial iron accumulation in cardiomyocytes can contribute to the pathogenesis of HF, 2) HF may be associated with increased mitochondrial iron, and 3) mitochondrial iron chelation may be an effective treatment against the development of HF (even in the absence of iron overload in the heart) (Figure). …”

“…In addition to the genetic disorders mentioned above, mitochondrial iron overload is also linked to doxorubicin-induced cardiomyopathy, and is associated with some mouse genetic models of spontaneous cardiomyopathy. 7 We recently demonstrated that mitochondrial iron increases during cardiac ischemia/reperfusion (I/R) injury, and that modulating baseline mitochondrial iron (i.e., without underlying iron overload) is sufficient to prevent I/R injury. 8 Furthermore, both human and animal studies have provided evidence for cardiomyocyte mitochondrial iron accumulation in HF.…”

“…8 Furthermore, both human and animal studies have provided evidence for cardiomyocyte mitochondrial iron accumulation in HF. Increased mitochondrial iron has been observed in mice with myocardial infarction- or hypertrophy-induced HF, 7 and in dog models of HF. In humans, end-stage HF is also associated with increased cardiac mitochondrial heme iron.…”

“…7 Even if iron levels are not increased in the heart of patients with HF, a reduction in baseline iron may reduce cellular oxidative stress and damage. 8 Thus, a number of human clinical studies have investigated the use of iron chelators as treatment for CVD.…”