Mice
To understand the underlying pathomechanisms leading to coronary artery disease animal models can be used to mimic the processes leading to the human disorder.
Mice became the most extensively used animal model mainly because of their short life cycle, short time frame of developing a disease and ease of genetic manipulation. However, mice do not develop atherosclerosis unless they are backcrossed to an atherogenic strain such as Apoe-KO, Ldlr-KO, or ApoE-Leiden mice.
At the ICG we have selected Adamts7, Ppap2b, Mras, Gucy1a3, Phactr1, Zc3hc1, Cxcl12, and Cyp17a1 to study the role of these CAD risk genes in mice.
Currently, heterozygous mice for each target risk gene are backcrossed to the strong pro-atherogenic background such as ApoE- or LDLR-KO to induce atherosclerosis within 2 months after feeding a high fat diet. Resulting mice will be characterized in-vivo for atherosclerosis, calcification, arterial stiffness, neo-intima formation, inflammation, and in-vitro using cell migration/proliferation.
Projects
Dr. hum. biol. Zouhair Aherrahrou
ADAMTS-7 is a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family. It was recently identified to be significantly associated with coronary artery disease using genome-wide association studies.
We generated Adamts7 Knockout mice and studied the effect of Adamts7 on neo-intima formation and atherosclerosis. ADAMTS-7 deficiency inhibits vascular smooth muscle cell migration and neointima formation (Kessler et al. 2015).
In addition, we also demonstrated the protective potential of ADAMTS7 deficiency on atherosclerosis.
Thus ADAMTS-7 inhibition is a promising target for atherosclerosis and restenosis.
Dr. hum. biol. Zouhair Aherrahrou
CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. CYP17A1 genetic variants are associated with coronary artery disease, myocardial infarction, and visceral and subcutaneous fat distribution.
In this project we aimed to investigate the function of CYP17A1 and its impact on atherosclerosis in mice. We generated the Cyp17a1 KO mice. In contrast to a previous publication reporting embryonic lethality in CYP17A1-deficient mice, our mice survived to adulthood. Both male and female Cyp17a1 KO mice are infertile and have abnormal plasma steroids. Plasma steroid analyses revealed a complete lack of testosterone in XY-KO mice.
Investigating Cyp17a1 deficient mice on an ApoE KO atherogenic background, we demonstrated the effects of Cyp17a1 on atherosclerosis.
The Cyp17a1 x ApoE dKO males were found to have more atherosclerotic lesions than ApoE KO controls, thus suggesting that the lack of testosterone is a risk factor in atherosclerosis (Aherrahrou et al. 2020).