Atherogenesis and vascular calcification in mice expressing the human LPA gene.

摘要

Background: Lp(a) lipoprotein (Lp(a)) contains polymorphic glycoprotein, apolipoprotein(a) (apo(a)) and low density lipoprotein (LDL). The extensive homology between apo(a) and plasminogen is believed to contribute to the pathogenicity of apo(a), but the precise mechanisms by which Lp(a) participates in atherogenesis is still unknown. We used LPA-yeast artificial chromosome (LPA-YAC) transgenic mice with or without the human APOB (hAPOB) gene to study pathogenicity of apo(a)/Lp(a) and illucidate its role in regulation of serum lipid levels. Methods: Middle-aged (1-year-old) mice were fed a control (AIN-76), a high-cholesterol (HC) or a high-cholesterol/high-fat (HCHF) diet for 7 weeks. For the study of serum total apo(a) and lipid levels, mice were sampled prior to the experiment, at 2 weeks and at 7 weeks when the animals were sacrificed. Hearts with ascending aorta were fixed in formalin, embedded in gelatine and prepared for sections on a cryostat. Livers were washed in ice cold saline and submergedin RNAlater trade mark buffer and stored at -70 degrees C until mRNA analysis. Results: Wild type mice fed the control diet did not develop aortic lesions. Presence of the LPA gene was sufficient to induce development of aortic lesions, but neither coexpression of the hAPOB gene nor feeding the HC diet or the HCHF diet augmented the development of aortic lesions in LPA-YAC transgenic mice. On the control diet transgenic females had larger aortic lesion size than transgenic males. Furthermore, aortic lesions in transgenic females were associated with calcification more often than in transgenic males. Serum total cholesterol levels were higher both in wild type and LPA-YAC transgenic males than in females mainly because of higher serum high-density lipoprotein cholesterol levels. HC and HCHF feeding had more pronounced effect on total cholesterol levels in LPA-YAC/hAPOB transgenic mice than in either wild type or LPA-YAC transgenic mice, due to increased low density lipoprotein cholesterol levels. Furthermore, these diets reduced serum total apo(a) levels in both transgenic mouse lines. Conclusion: Expression of the human LPA gene in mice is sufficient to trigger development of aortic lesions. Similar frequency of calcified lesions in LPA-YAC transgenic mice with or without hAPOB gene may suggest that apo(a) is the part of the Lp(a) molecule that causes aortic calcification. The basis for reduced serum total apo(a) level in response to cholesterol feeding is not clear, but interplay between LPA and factors involved in cholesterol or bile acid homeostasis is worth of future studies.