Metformin mediates cardioprotection against aging-induced ischemic necroptosis.
Aging Cell
; 19(2): e13096, 2020 02.
Article
in En
| MEDLINE
| ID: mdl-31944526
ABSTRACT
Necroptosis is crucially involved in severe cardiac pathological conditions. However, whether necroptosis contributes to age-related intolerance to ischemia/reperfusion (I/R) injury remains elusive. In addition, metformin as a potential anti-aging related injury drug, how it interacts with myocardial necroptosis is not yet clear. Male C57BL/6 mice at 3-4- (young) and 22-24 months of age (aged) and RIPK3-deficient (Ripk3-/- ) mice were used to investigate aging-related I/R injury in vivo. Metformin (125 µg/kg, i.p.), necrostatin-1 (3.5 mg/kg), and adenovirus vector encoding p62-shRNAs (Ad-sh-p62) were used to treat aging mice. I/R-induced myocardial necroptosis was exaggerated in aged mice, which correlated with autophagy defects characterized by p62 accumulation in aged hearts or aged human myocardium. Functionally, blocking autophagic flux promoted H/R-evoked cardiomyocyte necroptosis in vitro. We further revealed that p62 forms a complex with RIP1-RIP3 (necrosome) and promotes the binding of RIP1 and RIP3. In mice, necrostatin-1 treatment (a RIP1 inhibitor), RIP3 deficiency, and cardiac p62 knockdown in vivo demonstrated that p62-RIP1-RIP3-dependent myocardial necroptosis contributes to aging-related myocardial vulnerability to I/R injury. Notably, metformin treatment disrupted p62-RIP1-RIP3 complexes and effectively repressed I/R-induced necroptosis in aged hearts, ultimately reducing mortality in this model. These findings highlight previously unknown mechanisms of aging-related myocardial ischemic vulnerability p62-necrosome-dependent necroptosis. Metformin acts as a cardioprotective agent that inhibits this unfavorable chain mechanism of aging-related I/R susceptibility.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autophagy
/
Aging
/
Reperfusion Injury
/
Receptor-Interacting Protein Serine-Threonine Kinases
/
Necroptosis
/
Metformin
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Aging Cell
Year:
2020
Document type:
Article
Affiliation country:
China