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Published on: May 26, 2023
PCSK9 inhibition alleviates sepsis-induced myocardial dysfunction by facilitating PINK1/parkin-associated mitophagy
Jiancheng Lin1,2,3, Zetao Pan1,2,3, Jiayan Sun1,2,3
1Medical College of Soochow University, Suzhou, Jiangsu, China.
Introduction:
Sepsis-induced myocardial dysfunction (SIMD), also known as septic cardiomyopathy in sepsis patients is associated with worse prognosis and higher mortality compared to sepsis cases without SIMD. Early intervention and comprehensive management are crucial for improving survival, particularly in the early stages of sepsis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target in the cardiovascular system. While PCSK9 has been implicated in cardiovascular inflammation and injury, specific evidence regarding the potential of PCSK9 inhibition to mitigate SIMD remains limited.
Methods:
An in vivo mouse model of sepsis was established using cecal ligation and puncture (CLP), and SIMD was assessed through echocardiography and right ventricular systolic pressure measurements. For in vitro cellular SIMD models, lipopolysaccharide was administered to HL-1 and H9c2 cardiomyocytes. Data concerning apoptosis, inflammatory responses, oxidative stress, and mitophagy were evaluated across both models.
Results:
The SIMD models were successfully established both in vivo and in vitro. PCSK9 inhibition visibly attenuated myocardial dysfunction, cellular injury, apoptosis, inflammation, and oxidative stress, which was accompanied by enhanced mitophagic clearance. Furthermore, the application of Mdivi-1, a mitochondrial division inhibitor that impairs mitophagy, revealed that the cardioprotective effects of PCSK9 inhibition are at least partially dependent on the preservation of mitophagy. Mechanistically, PCSK9 inhibition appeared to facilitate mitophagic flux in SIMD, potentially via the PINK1/Parkin signaling pathway.
Conclusion:
These findings suggest that the protective effects of PCSK9 inhibition against SIMD are closely associated with the enhancement of mitophagy and the modulation of the PINK1/Parkin pathway. Furthermore, this intervention correlates with attenuated oxidative stress, inflammation, and apoptosis, ultimately offering a potential therapeutic strategy for myocardial injury.
