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Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence
- Source :
- Circ Res
- Publication Year :
- 2021
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2021.
-
Abstract
- Rationale: Patients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events. Objective: Define the molecular mechanisms underlying influenza virus–induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process. Methods and Results: Hearts from wild-type and necroptosis-deficient (MLKL [mixed lineage kinase domain-like protein]-KO) mice were dissected 12 days after initial influenza A virus (IAV) infection when viral titers were undetectable in the lungs. Immunofluorescence microscopy and plaque assays showed presence of viable IAV particles in the myocardium without generation of interferon responses. Global proteome and phosphoproteome analyses using high-resolution accurate mass-based LC-MS/MS and label-free quantitation showed that the global proteome as well as the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts in a strain-independent manner. Necroptosis-deficient mice had increased survival and reduced weight loss post-IAV infection, as well as increased antioxidant and mitochondrial function, indicating partial protection to IAV infection. These findings were confirmed in vitro by pretreatment of human and rat myocytes with antioxidants or necroptosis inhibitors, which blunted oxidative stress and mitochondrial damage after IAV infection. Conclusions: This study provides the first evidence that the cardiac proteome and phosphoproteome are significantly altered post–pulmonary influenza infection. Moreover, viral particles can persist in the heart after lung clearance, altering mitochondrial function and promoting cell death without active replication and interferon responses. Finally, our findings show inhibition of necroptosis or prevention of mitochondrial damage as possible therapeutic interventions to reduce cardiac damage during influenza infections. Graphic Abstract: A graphic abstract is available for this article.
- Subjects :
- 0301 basic medicine
Programmed cell death
Heart Diseases
Proteome
Physiology
media_common.quotation_subject
Necroptosis
030204 cardiovascular system & hematology
Mitochondrion
Proteomics
Bioinformatics
medicine.disease_cause
Article
Cell Line
Mice
03 medical and health sciences
0302 clinical medicine
Orthomyxoviridae Infections
medicine
Animals
Humans
Myocytes, Cardiac
media_common
business.industry
Convalescence
Phosphoproteomics
Phosphoproteins
Rats
Mice, Inbred C57BL
Oxidative Stress
030104 developmental biology
Influenza A virus
Cardiology and Cardiovascular Medicine
business
Protein Kinases
Oxidative stress
Subjects
Details
- ISSN :
- 15244571 and 00097330
- Volume :
- 128
- Database :
- OpenAIRE
- Journal :
- Circulation Research
- Accession number :
- edsair.doi.dedup.....85dd2a5a3ed6576bfa7e3eb0af7eab0d