Novel Mouse Model of Coronary Atherosclerosis With Myocardial Infarction: Insights Into Human CAD
Hong Chen1, Qing Wan1, Jianfeng Yang1
1State Key Laboratory of Cardiovascular Disease (H.C., Q.W., J.Y., H.R., C.X., P.X., X.Y., S.H., M.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.
Insights
Hypercholesterolemia combined with angiotensin II-induced hypertension synergistically accelerates coronary atherosclerosis. This occurs due to the coronary endothelium's vulnerability to angiotensin II and prostaglandin inhibition, creating a new mouse model for heart disease.
Area of Science:
- Cardiovascular Biology
- Atherosclerosis Research
- Mouse Models of Disease
Background:
- Coronary artery disease (CAD) is a chronic, multifactorial condition with acute events.
- The combined effects of hypercholesterolemia and hypertension on coronary atherosclerosis are not well understood.
Purpose of the Study:
- To investigate the synergistic impact of hypercholesterolemia and hypertension on coronary atherosclerosis development.
- To establish and utilize a novel mouse model (ApoE^SA/SA) for studying coronary atherosclerosis.
Main Methods:
- Generation of ApoE^SA/SA mice with inactivated ApoE/Scarb1 and inducible angiotensin II (Ang II).
- Assessment of coronary atherosclerosis using western diet and Ang II-induced hypertension.
- Comparative analysis of coronary vs. femoral artery responses and proteomic profiling.
Main Results:
- ApoE^SA/SA mice on a western diet developed mild coronary atherosclerosis and heart failure.
- Ang II-induced hypertension, but not norepinephrine-induced hypertension, drastically accelerated coronary atherogenesis.
- Coronary arteries showed increased susceptibility to Ang II, impaired endothelium-dependent dilation, and suppressed prostaglandin biosynthesis compared to femoral arteries.
Conclusions:
- Hypercholesterolemia and Ang II-induced hypertension synergistically promote coronary atherogenesis.
- Selective vulnerability of coronary endothelium-dependent vasodilation contributes to this effect.
- ApoE^SA/SA mice provide a valuable model for coronary atherosclerosis with spontaneous myocardial infarction.
Background:
Coronary artery disease is a chronic and multifactorial disease with acute manifestations. Little is known about the concomitant impact of hypercholesterolemia and hypertension on the development of coronary atherosclerosis.
Methods:
ApoE (apolipoprotein E) and Scarb1 (scavenger receptor class B, type I), both associated with human hypercholesterolemia, were inactivated in mice by inserting a Scarb1 knockdown cassette downstream of the ApoE promoter. Meanwhile, a doxycycline-inducible Ang II (angiotensin II) expression cassette was introduced. The resultant mutant mice (ApoESA/SA), isolated arteries, and pharmacological/genetic interventions were employed to assess the impacts of hypercholesterolemia and hypertension on coronary atherosclerosis and mechanisms.
Results:
ApoESA/SA mice developed mild coronary atherosclerosis with heart failure after chronic feeding with western diet. Strikingly, additional Ang II-induced hypertension, but not norepinephrine-induced hypertension, drastically accelerated coronary atherogenesis, exhibiting endothelial erosion, myeloid cell infiltration, spontaneous plaque rupture, and myocardial infarction, which was Ang II type 1 receptor-dependent. In contrast to this severe coronary atherosclerosis, femoral arteries were resistant to atherogenesis. Proteomic profiling revealed substantial differences in vasomotor reactivity and inflammation. Endothelium-dependent dilatation of coronary arteries was highly susceptible to the combination of hypercholesterolemia and hypertension compared with femoral arteries, and a similar vulnerability was also observed in human coronary arteries. Ex vivo exposure to Ang II markedly impaired endothelium-dependent dilatation in coronary arteries, but not in femoral arteries. Consistent with its less coronary atherogenic activity, norepinephrine dilated coronary arteries while constricting femoral arteries. Furthermore, dilatation of the coronary artery was more dependent on prostaglandins than that in femoral artery. Coronary prostaglandin biosynthesis was suppressed during atherogenesis and, conversely, an elevated coronary production of prostaglandins after methotrexate administration was associated with improved endothelial function and better cardiovascular survival.
Conclusions:
The combination of hypercholesterolemia and Ang II-induced hypertension exerts strong synergistic effects on coronary atherogenesis. This is attributable to a selective vulnerability of coronary endothelium-dependent vasodilator responses to Ang II exposure and prostaglandin inhibition. ApoESA/SA represents a novel and convenient mouse model of coronary atherosclerosis with spontaneous myocardial infarction.
