Molecular Mechanisms of Ferroptosis and Relevance to Cardiovascular Disease

Cells. 2022 Sep 1;11(17):2726. doi: 10.3390/cells11172726.

Abstract

Ferroptosis has recently been demonstrated to be a novel regulated non-apoptotic cell death characterized by iron-dependence and the accumulation of lipid peroxidation that results in membrane damage. Excessive iron induces ferroptosis by promoting the generation of both soluble and lipid ROS via an iron-dependent Fenton reaction and lipoxygenase (LOX) enzyme activity. Cytosolic glutathione peroxidase 4 (cGPX4) pairing with ferroptosis suppressor protein 1 (FSP1) and mitochondrial glutathione peroxidase 4 (mGPX4) pairing with dihydroorotate dehydrogenase (DHODH) serve as two separate defense systems to detoxify lipid peroxidation in the cytoplasmic as well as the mitochondrial membrane, thereby defending against ferroptosis in cells under normal conditions. However, disruption of these defense systems may cause ferroptosis. Emerging evidence has revealed that ferroptosis plays an essential role in the development of diverse cardiovascular diseases (CVDs), such as hemochromatosis-associated cardiomyopathy, doxorubicin-induced cardiotoxicity, ischemia/reperfusion (I/R) injury, heart failure (HF), atherosclerosis, and COVID-19-related arrhythmias. Iron chelators, antioxidants, ferroptosis inhibitors, and genetic manipulations may alleviate the aforementioned CVDs by blocking ferroptosis pathways. In conclusion, ferroptosis plays a critical role in the pathogenesis of various CVDs and suppression of cardiac ferroptosis is expected to become a potential therapeutic option. Here, we provide a comprehensive review on the molecular mechanisms involved in ferroptosis and its implications in cardiovascular disease.

Keywords: ROS; cardiovascular disease; ferroptosis; iron; lipid peroxidation; mitochondria.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19*
  • Cardiovascular Diseases*
  • Ferroptosis*
  • Humans
  • Iron / metabolism
  • Lipid Peroxidation
  • Reperfusion Injury*

Substances

  • Iron