Sortilin – a Novel Regulator of Microcalcification - Associates with Cardiovascular Risk in Humans

Background: Arterial calcification, particularly low-density microcalcification, predicts cardiovascular events. We showed that extracellular vesicles (EVs) contribute to microcalcification. Human GWAS studies linked sortilin... [ view full abstract ]

Background: Arterial calcification, particularly low-density microcalcification, predicts cardiovascular events. We showed that extracellular vesicles (EVs) contribute to microcalcification. Human GWAS studies linked sortilin and coronary artery calcification. Here, we assessed the role of sortilin in arterial calcification and as a surrogate serum marker for cardiovascular events.
Results: We demonstrated in vitro that sortilin controls the calcification potential of EVs by regulating the trafficking of tissue non-specific alkaline phosphatase (TNAP). Mass spectrometry identified a calcification-dependent phosphorylation within the C-terminal domain. We assessed the effects of genetic deletion of sortilin (Sort1) in Ldlr-deficient mice consuming a high-fat, high-cholesterol diet. Sort1-/-Ldlr-/- mice exhibited 80% lower aortic calcification as compared to control Ldlr-/- mice (fluorescence reflectance imaging of a NIRF calcium tracer, p<0.01). Sort1-/-Ldlr-/- mice showed 88% lower extracted aortic calcium (p<0.05). Histological analysis of aortic arches revealed decreased TNAP activity and reduced microcalcification. In a community-based cohort of elderly men (n=830), abdominal aortic calcification (AAC) was assessed by dual energy X-ray absorptiometry. Serum sortilin levels were measured by ELISA. After adjustment for confounders, sortilin levels correlated positively with severe AAC. The highest sortilin quartile associated with higher odds of severe AAC even in men without ischemic heart disease (OR=2.2, p<0.05). Among 745 men followed up prospectively for 7.9 years, major adverse cerebro-cardiovascular events occurred in 76 men. Elevated serum sortilin associated with 3.7-fold higher event risk (adjusted for confounders, p<0.001).
Conclusions: Sortilin is a novel therapeutic target to modulate the formation of microcalcification and a biomarker of both aortic calcification and cardiovascular risk.