LRP3 promotes angiogenesis after ischemia and affects the survival and prognosis of patients with myocardial infarction
C ZhaiAbstract
Background
Myocardial infarction is one of the most high-risk cardiovascular events, and promoting angiogenesis after ischemia is an effective strategy to improve ventricular remodeling1. However, the precise mechanism of regulating cardiac angiogenesis is still unclear, and clinical treatment methods are limited. As a member of lipoprotein receptor family, the role of LRP3 in cardiovascular repair and genetic regulation is rarely reported2.
Objective
To investigate whether genetic variation in LRP3 is associated with long-term prognosis in myocardial infarction patients and to determine its role in promoting post-ischemic angiogenesis, thereby evaluating its therapeutic potential.
Methods
The correlation between LRP3 gene single nucleotide polymorphism and long-term mortality (follow-up for ten years) was analyzed by using the whole exon sequencing data of patients with myocardial infarction. To detect the expression changes of LRP3 in heart tissue after myocardial infarction. LRP3 knockout mice were constructed, and myocardial infarction model was established. Cardiac function, myocardial fibrosis and cardiac perfusion were evaluated by echocardiography, Masson staining and 18F-FDG PET/CT. Knock down LRP3 in HUVEC to detect the changes of endothelial cells' tube-forming and migration ability.
Results
The whole exon sequencing showed that the locus rs17848213 of LRP3 gene was significantly correlated with all-cause death and cardiac death after myocardial infarction, and the risk of long-term death was significantly reduced in those who carried risk alleles (Figure 1A-B). The expression level of LRP3 was significantly down-regulated in both human and mouse infarcted hearts (Figure 2A-C). Compared with the control group, the myocardial function of LRP3 knockout mice deteriorated more significantly (Figure 2E), cardiac perfusion decreased (Figure 2F) and myocardial fibrosis worsened (Figure 2D). In vitro, knocking down LRP3 significantly inhibited the tube formation and migration ability of HUVEC.
Conclusion
Genetic variation of LRP3 gene is an independent predictor of long-term death risk in patients with myocardial infarction; LRP3 plays a protective role in the heart by promoting angiogenesis after ischemia. Targeting LRP3 is expected to be a new strategy to improve the prognosis of myocardial infarction.Figure1Figure2