Arterial Stiffening and Calcification Associated with Abnormal Lysosomal Positioning and Exosome Secretion in Mice Lacking Mucolipin 1 Gene

Abstract

Arterial calcification is a highly regulated cellular process that is characterized by the pathological mineral deposition leading to reduced arterial compliance. The aim of the present study was to investigate whether mucolipin 1 gene contributes to lysosomal positioning and exosome secretion which may results in phenotype change in SMCs during arterial medial calcification (AMC). In mucolipin 1 gene knock out (KO) mice, a high dose of Vit D (500,000 IU/kg/day) resulted in increased aortic calcification compared to their wild type littermates, which was accompanied by downregulation of SM22‐a and upregulation of RUNX2 and osteopontin in the arotic media, indicating phenotypic switch to osteogenic. Furthermore, we observed decreased colocalization of lysosome marker (Lamp‐1) with lysosome coupling marker (Rab 7 and ALG‐2) in the arterial wall of mucolipin 1 KO mice as compared to their wild type littermates. In addition, mucolipin 1 KO mice showed increased expression of exosome markers, CD63 and annexin‐II (AnX2), in the arterial medial wall, which was associated with reduced co‐localization of lysosome marker (Lamp‐1) with multivesicular body (MVB) marker (VPS16). This suggests reduction of the lysosome‐MVB interactions. Furthermore, we found significantly increased exosomes in the plasma of mucolipin 1 KO mice as compared to the wild type littermates. Functionally, in mucolipin 1 KO mice pulse wave velocity (PWV) significantly increased and Vit D treatment further enhance such stiffening. All these data indicate that mucolipin‐1 gene deletion leads to abnormal lysosome positioning and exosome secretion in the arterial wall, which may contribute to the arterial stiffness during the development of AMC.Support or Funding Information(Supported by NIH grants HL057244, HL075316 and DK120491)