Macrophage-specific expression of human lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein E knockout mice but not in C57BL/6 mice

Transgenic mice with macrophage-specific expression of human (hu) lipoprote in lipase (LPL) were generated to determine the contribution of macrophage LPL to atherogenesis. Macrophage specificity was accomplished with the scav enger receptor A promoter. Complete characterization demonstrated that macr ophages from these mice expressed huLPL mRNA and secreted enzymatically act ive huLPL protein. Expression of huLPL was macrophage specific, because tot al RNA isolated from heart, thymus, lung, liver, muscle, and adipose tissue s was devoid of huLPL mRNA. Macrophage-specific expression of huLPL did not exacerbate lesions in aortas of C57BL/6 mice even after 32 weeks on an ath erosclerotic diet. However, when expressed in apolipoprotein E knockout bac kground, the extent of occlusion in the aortic sinus region of male huLPL mice increased 51% (n = 9 to 11, P < 0.002) compared with huLPL- mice afte r they had been fed a Western diet for 8 weeks. The proatherogenic effect o f macrophage LPL was confirmed in serial sections of the aorta obtained aft er mice had been fed a Western diet for 3 weeks. By immunohistochemical ana lysis, huLPL protein was detected in the lesions of huLPL + mice but not in huLPL- mice. Our results establish that macrophage LPL accelerates atheros clerosis in male apolipoprotein E knockout mice.