PCSK9 Knockdown Can Improve Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy

Abstract

Background and Aim: This study aims to investigate the effect and mechanism of proprotein convertase subtilisin/Kexin type 9 (PCSK9) on myocardial ischemia-reperfusion injury (MIRI) and provide a reference for clinical prevention and treatment of acute myocardial infarction (AMI).METHODS: We established a rat myocardial ischemia/reperfusion (I/R) model and AC16 hypoxia/reoxygenation (H/R) model. A total of 48 adult male Sprague-Dawley rats were randomly assigned to three groups (n=16): control, I/R, and I/R +SiRNA. In I/R and I/R +siRNA groups, myocardial ischemia was induced via occlusion of the left anterior descending branch (LAD) of the coronary artery in rats in I/R group for 0.5 h and reperfused for three days. To assess the myocardial injury, the rats were subjected to an electrocardiogram (ECG), cardiac function tests, cardiac enzymes analysis, and 2,3,5triphenyl tetrazolium chloride (TTC)/Evan Blue (EB) staining. Meanwhile, hematoxylin-eosin (HE) staining was used to detect morphological changes in cardiomyocytes in each group, and the level of myocardial brosis was quanti ed using Masson trichrome staining. Differences in the expression of autophagylevel proteins and Bcl-2/adenovirus E1B 19-kDa interacting protein (Bnip3) signaling-related proteins were determined by protein blotting. RESULTS: I/R and H/R injury increased the expression level of PCSK9, activated the downstream Bnip3, and subsequently triggered autophagy. In vitro and in vivo experimental studies revealed that siRNA knockdown of PCSK9 resulted in reduced expression of the autophagic protein Beclin-1, light chain 3 (LC3) compared to normal control-treated cells and control-operated groups. Simultaneously, the presentation of the autophagic pathway Bnip3 was downregulated. Furthermore, PCSK9-mediated small interfering RNA (siRNA) group injected into the left ventricular wall signi cantly improved cardiac function and myocardial infarct size, as well as the expression of mRNA of Recombinant Human Interleukin-1β IL-1β. Moreover, Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)was signi cantly downregulated and reduced the in ammatory response compared with the I/R group.CONCLUSIONS: In ischemic/hypoxic circumstances, PCSK9 expression was dramatically increased. PCSK9 knockdown alleviated MIRI via the Bnip3-mediated autophagic pathway and improved in ammatory response, myocardial infarct size, and cardiac function.

Mitochondrial Dysfunction in Cardiac Diseases and Therapeutic Strategies

“…PCSK9 knockdown in adult rats alleviated myocardial injury induced by occlusion of the left anterior descending (LAD) branch. This protective effect was attributed to the repression of the Bnip3 autophagy pathway and inhibition of the inflammatory response [126].…”

“…In an ischemic or hypoxic heart, the expression of many mitochondria-related enzymes and genes is increased, which causes mitochondrial dysfunction in cardiac muscle cells leading to myocardial damage [124][125][126]. In response to ischemic stress, proprotein convertase subtilisin/kexin type 9 (PCSK9) expression is strongly upregulated in the border region of infarcted mouse hearts, and autophagy ensues [124].…”

PCSK9 in extrahepatic tissues: What can we expect from its inhibition?

“…It is noteworthy that high expression of PCSK9 after myocardial infarction promotes pro-inflammatory M1 macrophage polarisation associated with poor myocardial repair, whereas PCSK9 deficiency promotes anti-inflammatory M2 macrophage polarisation and better protection against myocardial injury (54). Inhibition of PCSK9 has been shown to ameliorate myocardial injury after ischaemia/reperfusion by inhibiting autophagy and inflammation (55).…”

miR-873-5p Suppression Reinvigorates Aging Mesenchymal Stem Cells and Improves Cardiac Repair after Myocardial Infarction

“…Autophagy serves a crucial role in maintaining intracellular homeostasis by eliminating harmful cytoplasmic components through autolysosomes . Recent studies have revealed that stem cells, including MSCs, experience cellular senescence at an early stage, a phenomenon closely associated with impaired autophagy function. , MSCs obtained from older donors exhibited compromised autophagy capabilities.…”