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Anti-Ferroptotic Treatment Deteriorates Myocardial Infarction by Inhibiting Angiogenesis and Altering Immune Response
Rebecca A Stairley1, Allison M Trouten1, Shuang Li1,2
1Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Insights
In injured hearts, ferroptosis (iron-dependent cell death) aids healing by releasing growth factors. Inhibiting this regulated cell death impairs cardiac function and regeneration.
Area of Science:
- Cardiology
- Cell Biology
- Regenerative Medicine
Background:
- Mammalian heart regeneration is limited, with cardiac diseases causing cardiomyocyte loss via regulated cell death (RCD).
- Ferroptosis, an iron-dependent RCD, is identified as a primary mechanism of cardiomyocyte death in injured hearts.
- Understanding RCD mechanisms is vital for developing heart regeneration therapies.
Purpose of the Study:
- To investigate the underlying mechanisms of ferroptosis preference in cardiomyocytes.
- To evaluate the therapeutic potential of inhibiting ferroptosis in cardiac injury models.
Main Methods:
- Administration of anti-ferroptotic reagents to infarcted mouse hearts.
- Assessment of neonatal heart regeneration and juvenile cardiac function.
- Analysis of immune and angiogenic responses in regenerating mouse hearts.
Main Results:
- Anti-ferroptotic treatment did not enhance neonatal heart regeneration and worsened juvenile cardiac function.
- Ferroptotic cardiomyocytes were found to support wound healing by secreting pro-angiogenic factors.
- Inhibition of ferroptosis altered immune and angiogenic responses in the regenerating heart.
Conclusions:
- Cardiomyocytes exhibit a preference for ferroptosis, which plays a beneficial role in cardiac wound healing.
- Targeting ferroptosis requires careful consideration, as its inhibition can be detrimental to cardiac function and regeneration.
- Findings offer insights for designing effective anti-cell-death therapies for heart disease, emphasizing the nuanced role of ferroptosis.
Abstract:
Mammalian cardiomyocytes have limited regenerative ability. Cardiac disease, such as congenital heart disease and myocardial infarction, causes an initial loss of cardiomyocytes through regulated cell death (RCD). Understanding the mechanisms that govern RCD in the injured myocardium is crucial for developing therapeutics to promote heart regeneration. We previously reported that ferroptosis, a non-apoptotic and iron-dependent form of RCD, is the main contributor to cardiomyocyte death in the injured heart. To investigate the mechanisms underlying the preference for ferroptosis in cardiomyocytes, we examined the effects of anti-ferroptotic reagents in infarcted mouse hearts. The results revealed that the anti-ferroptotic reagent did not improve neonatal heart regeneration, and further compromised the cardiac function of juvenile hearts. On the other hand, ferroptotic cardiomyocytes played a supportive role during wound healing by releasing pro-angiogenic factors. The inhibition of ferroptosis in the regenerating mouse heart altered the immune and angiogenic responses. Our study provides insights into the preference for ferroptosis over other types of RCD in stressed cardiomyocytes, and guidance for designing anti-cell-death therapies for treating heart disease.
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