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[Preprint]. 2024 Oct 24:2024.04.24.590907.
doi: 10.1101/2024.04.24.590907.

Ferroptosis Inhibition Combats Metabolic Derangements and Improves Cardiac Function in Pulmonary Artery Banded Pigs

Felipe Kazmirczak  1 , Ryan Moon  1 , Neal T Vogel  1 , Walt Tollison  2 , Matt T Lahti  2 , John P Carney  2 , Jenna B Mendelson  3 , Todd Markowski  4 , LeeAnn Higgins  4 , Kevin Murray  4 , Candace Guerrero  4 , Kurt W Prins  1
Affiliations

Ferroptosis Inhibition Combats Metabolic Derangements and Improves Cardiac Function in Pulmonary Artery Banded Pigs

Felipe Kazmirczak et al. bioRxiv. .

Update in

Abstract

Right heart failure (RHF) is a leading cause of mortality in multiple cardiovascular diseases and preclinical and human data suggest impaired metabolism is a significant contributor to right-sided cardiac dysfunction. Ferroptosis is a nonapopotic form of cell death driven by impaired metabolism. Rodent data suggests ferroptosis inhibition can restore mitochondrial electron transport chain function and enhance cardiac contractility in left heart failure models, but the effects of ferroptosis inhibition in translational large animal models of RHF are unknown. Here, we showed ferrostatin-1 mediated ferroptosis antagonism improve right heart structure and function in pulmonary artery banded pigs. Molecularly, ferrostatin-1 restored mitochondrial cristae structure and combatted downregulation of electron transport chain proteins. Metabolomics and lipidomics analyses revealed ferrostatin-1 improved fatty acid metabolism. Thus, these translational data suggest ferroptosis may be a therapeutic target for RHF.

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Figures

Figure 1:
Figure 1:. Ferrostatin-1 Treatment Improves Right Ventricular Structure and Function in Pulmonary Artery Banded Pigs.
(A) Representative four-chamber cardiac magnetic resonance images in end-systole and end-diastole of control PAB-Vehicle, and PAB-Fer-1 animals. (B) Blinded quantification of right ventricular ejection fractions, p-values determined by one-way ANOVA with Tukey’s multiple comparison test. Ferroptosis inhibition counteracted RV dilation (C), p-values determined by one-way ANOVA with Tukey’s multiple comparison test and increased right atrial ejection fraction (D), p-values determined by Kruskal-Wallis test and Dunn’s multiple comparisons test.
Figure 2:
Figure 2:. Ferrostatin-1 Counteracts Mitochondrial Metabolic Dysregulation in the RV of PAB Pigs.
(A) Hierarchical cluster analysis of mitochondrial enrichments. (B) KEGG pathway analysis of the top 250 proteins that differentiated the three groups (left) and hierarchical cluster analysis of protein subunit abundances of oxidative phosphorylation proteins (right). (C) Hierarchical cluster analysis of total metabolites/lipids in RV specimens. (D) Hierarchical cluster analysis of triacylglycerides (TG), diacylglycerides (DG), and acylcarnitines. Ferroptosis inhibition partially prevented the reduction of TG, DG, and acylcarntines in RV samples.
See this image and copyright information in PMC

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