Ferroptosis in heart failure

Abstract

With its complicated pathobiology and pathophysiology, heart failure (HF) remains an increasingly prevalent epidemic that threatens global human health. Ferroptosis is a form of regulated cell death characterized by the iron-dependent lethal accumulation of lipid peroxides in the membrane system and is different from other types of cell death such as apoptosis and necrosis. Mounting evidence supports the claim that ferroptosis is mainly regulated by several biological pathways including iron handling, redox homeostasis, and lipid metabolism. Recently, ferroptosis has been identified to play an important role in HF induced by different stimuli such as myocardial infarction, myocardial ischemia reperfusion, chemotherapy, and others. Thus, it is of great significance to deeply explore the role of ferroptosis in HF, which might be a prerequisite to precise drug targets and novel therapeutic strategies based on ferroptosis-related medicine. Here, we review current knowledge on the link between ferroptosis and HF, followed by critical perspectives on the development and progression of ferroptotic signals and cardiac remodeling in HF.

Keywords: Ferroptosis; Glutathione homeostasis; Heart failure; Iron metabolism; Lipid metabolism.

Figure 1.. Mechanisms of ferroptosis.

Ferroptosis is characterized by the iron-dependent lethal lipid peroxidation in the membrane system. Metabolism of iron, lipid and cholesterol play important roles in the multiple process of ferroptosis. Cellular antioxidant systems neutralizing lipid peroxidation can be considered as ferroptosis defense mechanisms, including system Xc/GPX4, GCH1-/BH4, FSP1/CoQ10, FSP1/Vitamin K, mitochondria DHODH/CoQH2 axis. In addition, ferroptosis inducers (Erastin [1]; IKE, Imidazole Ketone Erastin [44]; Sulfasalazine [45, 46]; Auranofin[32]; BSO, Buthionine Sulfoximine [47]; CH004 [48]; APAP, Acetaminophen [49]; RSL3 [50]; ML162 [51]; ML210 [52]; FIN56 [53]; Brequinar [46];IFSP1 [35]; FINO2 [54]; t-BuOOH [55]; Dihydroartemisinin [56]) or inhibitors (Iron Chelator: DFO, Deferoxamine [1]; DXZ, Dexrazoxane [57]; DFX, Deferasirox [5]; DFP, Deferiprone [58]; Autophagy inhibitors [59]; Sulforaphane [60]; Compound 968 [61]; NAC [1]; Compound 3F [62]; ACSL4 inhibitors [63]; (R)-HTS-3 [64]; Aloxs inhibitors [65];Fer-1, Ferrostatin-1 [1]; LIP1, Liproxstatin-1[66]; UAMC-3203 [67]; Vitamin E [66]) are summarized and shown in red or blue respectively. ACSL 3/4, acyl-CoA synthetase long chain family member 3/4; AKR1C/D, aldosterone reductase family 1C/D; ALOXs, arachidonate lipoxygenase-s; BH4/BH2, tetrahydrobiopterin/ dihydrobiopterin; CHMP5/6, charged multivesicular body protein 5/6; CISD1, CDGSH iron sulfur domain 1; COQ₁₀, coenzyme Q₁₀; DMT1, divalent metal transporter 1; ESCRT III, endosomal sorting complex required for transport III; FPN; ferroportin; FSP1, ferroptosis suppressor protein 1; FTMT, mitochondrial ferritin; GCH1, GTP Cyclohydrolase 1; GPX4, Glutathione Peroxidase 4; GSH, glutathione; HO-1, heme oxygenase 1; LIP, labile iron pool; LPCAT 3, Lysophosphatidylcholine Acyltransferase 3; NCOA4, nuclear receptor coactivator 4; NTBI, non-transferrin-bound iron; PCBP1, poly(rC)-binding protein 1;POR, cytochrome P450 oxidoreductase; SCD1, stearoyl-CoA desaturase1; RNF217, ring finger protein 217; Se, selenium; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; SLC39A14; solute carrier family 39 member 14; SLC25A39, solute carrier family 25 member 39; STEAP 3, steap3 metalloreductase; TF, transferrin; TFR1, transferrin receptor 1; TRPML1, transient receptor potential channel mucolipin 1

Figure 2.. The role of ferroptosis in the pathophysiological development of heart failure.

Multiple physiological events ranging from I/R injury to diabetes can cause an oxidative dysfunctional state resulting in ferroptosis. Cell death resulting from ferroptosis in the heart plays a key role in the onset of cardiomyopathy and heart failure. ROS, reactive oxygen species; PLOOH, hydroperoxy-phospholipid; MDA, malondialdehyde; GPX4, Glutathione Peroxidase 4; FSP1, ferroptosis-suppressor-protein 1; GCH1, GTP Cyclohydrolase 1; BH4, tetrahydrobiopterin; Fer-1, Ferrostatin-1; Lip-1, Liproxstatin-1; DFO, deferoxamine; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction.