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Updated: Feb 10, 2026
Myocardial Infarction and Functional Outcome Assessment in Pigs
Published on: April 25, 2014
PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of
Zufeng Ding1,2,3, Xianwei Wang1,2, Shijie Liu1
1Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is elevated in heart attacks, worsening cardiac function and autophagy. Inhibiting PCSK9 reduces infarct size and improves heart function by decreasing autophagy.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Cellular Biology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a new therapy for hypercholesterolemia and cardiovascular diseases.
- The role of PCSK9 in cardiac ischemia, infarct size, cardiac function, and autophagy remains unclear.
Purpose of the Study:
- To investigate the role of PCSK9 in regulating infarct size, cardiac function, and autophagy during myocardial ischemia.
- To determine if PCSK9 inhibition can mitigate ischemia-induced cardiac damage.
Main Methods:
- Mice hearts underwent left coronary artery (LCA) occlusion to induce ischemia.
- Wild-type mice were pre-treated with PCSK9 inhibitors (Pep2-8, EGF-A) or used PCSK9 gene knockout mice.
- Cultured mouse cardiomyocytes were exposed to hypoxia, and treated with recombinant PCSK9 or PCSK9 siRNA.
Main Results:
- PCSK9 was highly expressed in the border zone of infarcts, associated with contractile dysfunction and autophagy in wild-type mice.
- PCSK9 inhibition or gene deficiency significantly reduced infarct size and improved cardiac function.
- PCSK9 inhibition markedly reduced autophagy; hypoxia induced PCSK9 and autophagy in cardiomyocytes, which was blocked by HIF-1α siRNA.
- Recombinant PCSK9 increased autophagy, while PCSK9 siRNA reduced it in hypoxic cardiomyocytes, suggesting PCSK9's role in autophagy regulation via the ROS-ATM-LKB1-AMPK axis.
- Human hearts with recent infarcts showed similar PCSK9 and autophagy expression patterns.
Conclusions:
- PCSK9 is upregulated in ischemic hearts and plays a critical role in determining infarct size, cardiac function, and autophagy.
- Targeting PCSK9 presents a potential therapeutic strategy for managing ischemia-related cardiac damage and dysfunction.
Aims:
Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. This study determined if PCSK9 can regulate infarct size, cardiac function, and autophagy during ischaemia.
Methods And Results:
Mice hearts were subjected to left coronary artery (LCA) occlusion. There was intense expression of PCSK9 in the zone bordering the infarct area in association with marked cardiac contractile dysfunction in the wild-type mice. This region also revealed intense autophagy. To assess the role of PCSK9 in the evolution of infarct size and function and development of autophagy, we used wild-type mice pre-treated with two different PCSK9 inhibitors (Pep2-8 and EGF-A) or mice lacking PCSK9 gene. Both strategies resulted in smaller infarcts and improved cardiac function following LCA ligation. PCSK9 inhibition also markedly reduced autophagy. Relationship between myocardial ischaemia and PCSK9 expression and autophagy was examined in cultured mouse cardiomyocytes. Exposure of cardiomyocytes to hypoxia resulted in prompt PCSK9 expression and autophagy signals; both were blocked by HIF-1α siRNA. Further, treatment of cardiomyocytes with recombinant PCSK9 during hypoxia induced, and treatment with PCSK9 siRNA reduced, autophagy suggesting a possible role of PCSK9 in the determination of autophagy. Other studies revealed activation of ROS-ATM-LKB1-AMPK axis as a possible mechanism of PCSK-induced autophagy. Hearts of humans with recent infarcts also showed expression of PCSK9 and autophagy in the border zone-similar to that in the infarcted mouse heart.
Conclusion:
PCSK9 is up-regulated in the ischaemic hearts and determines development of infarct size, cardiac function, and autophagy.
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