Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs
| Autor: | Jesús Vázquez, Jesper M. Jensen, Erling Falk, K. Ravlo, Peter Bie, Martin Bødtker Mortensen, Zahra P. Nasr, Rozh H Al-Mashhadi, Ahmed Ludvigsen Al-Mashhadi, Johan Palmfeldt, Esmeralda A. Lewis, Daniel Kjær, Emilio Camafeita, Jacob F. Bentzon, Zheer Al-Mashhadi, Bjarne L. Nørgaard |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
hypertension proteome 030204 cardiovascular system & hematology Coronary artery disease 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine low-density lipoproteins 030212 general & internal medicine Coronary atherosclerosis Computed tomography angiography medicine.diagnostic_test business.industry PCSK9 medicine.disease Coronary arteries Stenosis medicine.anatomical_structure chemistry Low-density lipoprotein minipigs Cardiology atherosclerosis Cardiology and Cardiovascular Medicine business coronary artery disease Artery |
| Zdroj: | Al-Mashhadi, R H, Al-Mashhadi, A L, Nasr, Z P, Mortensen, M B, Lewis, E A, Camafeita, E, Ravlo, K, Al-Mashhadi, Z, Kjær, D W, Palmfeldt, J, Bie, P, Jensen, J M, Nørgaard, B L, Falk, E, Vázquez, J & Bentzon, J F 2021, ' Local Pressure Drives Low-Density Lipoprotein Accumulation and Coronary Atherosclerosis in Hypertensive Minipigs ', Journal of the American College of Cardiology, vol. 77, no. 5, pp. 575-589 . https://doi.org/10.1016/j.jacc.2020.11.059 |
| DOI: | 10.1016/j.jacc.2020.11.059 |
| Popis: | Background The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries. Objectives This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms. Methods Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)D374Y Yucatan minipigs for >1 year. Caudal pressures remained normal. Results Under hypercholesterolemic conditions in PCSK9D374Y transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries. Conclusions Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins. Background: The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries. Objectives: This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms. Methods: Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)D374Y Yucatan minipigs for >1 year. Caudal pressures remained normal. Results: Under hypercholesterolemic conditions in PCSK9D374Y transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries. Conclusions: Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|