PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy.

Abstract

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.

• Authors: Zufeng Ding, Xianwei Wang, Shijie Liu, Jiwani Shahanawaz, Sue Theus, Yubo Fan, Xiaoyan Deng, Sichang Zhou, Jawahar L Mehta
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 114 Issue 13 Pg. 1738-1751 (11 01 2018) ISSN: 1755-3245 [Electronic] England
• PMID: 29800228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Autophagy-Related Proteins
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Inflammation Mediators
• PCSK9 Inhibitors
• RNA, Small Interfering
• Reactive Oxygen Species
• Receptors, LDL
• Serine Proteinase Inhibitors
• PCSK9 protein, human
• Pcsk9 protein, mouse
• Proprotein Convertase 9

Topics

• Aged
• Animals
• Autophagy (drug effects)
• Autophagy-Related Proteins (metabolism)
• Cell Hypoxia
• Cells, Cultured
• Disease Models, Animal
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Inflammation Mediators (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Myocardial Contraction (drug effects)
• Myocardial Infarction (enzymology, pathology, physiopathology, prevention & control)
• Myocardium (enzymology, pathology)
• PCSK9 Inhibitors
• Proprotein Convertase 9 (deficiency, genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Receptors, LDL (genetics, metabolism)
• Serine Proteinase Inhibitors (pharmacology)
• Signal Transduction
• Ventricular Function, Left (drug effects)