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Published on: September 28, 2015
Prior renovascular hypertension does not predispose to atherosclerosis in mice
Martin Bødtker Mortensen1, Line Nilsson2, Tore G Larsen2
1Department of Clinical Medicine, Aarhus University, Denmark; Department of Cardiology, Aarhus University Hospital, Denmark.
Insights
Hypertension does not cause lasting atherosclerosis changes in mice after blood pressure normalizes. Atherosclerosis risk from hypertension only occurs when high blood pressure and high cholesterol overlap.
Area of Science:
- Cardiovascular Science
- Renal Medicine
- Genetics
Background:
- Hypertension is a key risk factor for atherosclerotic cardiovascular disease (ASCVD).
- Antihypertensive drugs reduce ASCVD risk, but residual risk suggests hypertension causes chronic pro-atherosclerotic changes.
- This study investigated if hypertension induces persistent atherosclerosis susceptibility in mice.
Purpose of the Study:
- To test if hypertension increases atherosclerosis susceptibility in mice even after blood pressure returns to normal.
- To determine if hypertension causes chronic changes that promote atherosclerosis development.
Main Methods:
- Used the 2-kidney, 1-clip (2K1C) technique to induce renovascular hypertension in mice.
- Overexpressed the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene to induce hypercholesterolemia and atherosclerosis.
- Investigated atherosclerosis development in mice with sustained hypertension and in those with prior hypertension followed by normotension.
Main Results:
- In PCSK9 transgenic mice, 2K1C hypertension significantly increased atherosclerotic lesion area compared to sham controls.
- In wild-type mice, prior 2K1C hypertension followed by normotension did not result in significantly different atherosclerotic lesion areas compared to controls.
- These findings indicate that hypertension promotes atherosclerosis only during the period of elevated blood pressure when coinciding with hypercholesterolemia.
Conclusions:
- Renovascular hypertension in mice does not induce pro-atherogenic changes that persist after hypertension is resolved.
- Hypertension promotes atherogenesis only when it temporally coincides with hypercholesterolemia.
Background:
Hypertension is a major risk factor for development of atherosclerotic cardiovascular disease (ASCVD). Although lowering blood pressure with antihypertensive drugs reduces the increased risk of ASCVD, residual increased risk still remains, suggesting that hypertension may cause chronic changes that promote atherosclerosis. Thus, we tested the hypothesis that hypertension increases the susceptibility to atherosclerosis in mice even after a period of re-established normotension.
Methods:
We used the 2-kidney, 1-clip (2K1C) technique to induce angiotensin-driven renovascular hypertension, and overexpression of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene to cause severe hypercholesterolemia and atherosclerosis.
Results:
First, we performed 2K1C (n = 8) or sham surgery (n = 9) in PCSK9 transgenic mice before they were fed a high fat diet for 14 weeks. As expected, 2K1C did not affect cholesterol levels, but induced cardiac hypertrophy and significantly increased the atherosclerotic lesion area compared to sham mice (1.8 fold, p < 0.01). Next, we performed 2K1C (n = 13) or sham surgery (n = 14) in wild-type mice but removed the clipped/sham-operated kidney after 10 weeks to eliminate hypertension, and subsequently induced hypercholesterolemia by way of adeno-associated virus-mediated hepatic gene transfer of PCSK9 combined with high-fat diet. After 14 weeks of hypercholesterolemia, atherosclerotic lesion areas were not significantly different in mice with or without prior 2K1C hypertension (0.95 fold, p = 0.35).
Conclusion:
Renovascular hypertension in mice does not induce pro-atherogenic changes that persist beyond the hypertensive phase. These results indicate that hypertension only promotes atherogenesis when coinciding temporally with hypercholesterolemia.
