Abstract
Background: Hypertension is a major risk factor for atherosclerotic disease. However, it is still not clear whether mechanical stress caused by hypertension directly affects the atherosclerotic development in the aorta and coronary arteries. Objectives and Methods: We generated a hypertensive (HTN) rabbit model by surgical removal of the left kidney and partial ligation of the right renal artery. After a 16-week cholesterol diet, we compared aortic and coronary atherosclerosis of HTN rabbits with those of normotensive rabbits. Results: Hypertension did not affect lipid and apolipoprotein levels in plasma but led to a 3.0-fold increase in aortic atherosclerosis and a 1.7-fold increase in coronary atherosclerosis compared with control rabbits. Enhanced atherosclerosis in HTN rabbits was caused by significant increases in macrophages and smooth muscle cells in the lesions. Furthermore, oxidized LDL contents in the lesions were significantly increased in HTN rabbits. In addition, HTN rabbits exhibited prominent hyaline arteriolosclerosis in coronary arterioles. Conclusions: These results indicate that hyper tension not only enhances atherosclerosis in large arteries including the aorta and coronary arteries but also affects hyaline arteriolosclerosis in small arteries.
References
1.
Libby
P
, Ridker
PM
, Hansson
GK
. Progress and challenges in translating the biology of atherosclerosis
. Nature
. 2011
May
;473
(7347
):317
–25
.
[PubMed]
0028-08362.
Sowers
JR
, Epstein
M
, Frohlich
ED
. Diabetes, hypertension, and cardiovascular disease: an update
. Hypertension
. 2001
Apr
;37
(4
):1053
–9
.
[PubMed]
0194-911X3.
Yusuf
S
, Hawken
S
, Ounpuu
S
, Dans
T
, Avezum
A
, Lanas
F
, et al; INTERHEART Study Investigators
. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study
. Lancet
. 2004
Sep
;364
(9438
):937
–52
.
[PubMed]
0140-67364.
Aha
A
. National Heart L, Blood I, Smith SC, Jr., Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pearson T, Pfeffer MA, Taubert KA: AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update endorsed by the National Heart, Lung, and Blood Institute
. J Am Coll Cardiol
. 2006
;47
:2130
–9
.0735-10975.
Franco
OH
, Peeters
A
, Bonneux
L
, de Laet
C
. Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women: life course analysis
. Hypertension
. 2005
Aug
;46
(2
):280
–6
.
[PubMed]
0194-911X6.
Chobanian
AV
. The influence of hypertension and other hemodynamic factors in atherogenesis
. Prog Cardiovasc Dis
. 1983
Nov-Dec
;26
(3
):177
–96
.
[PubMed]
0033-06207.
Goldblatt
H
, Lynch
J
, Hanzal
RF
, Summerville
WW
. Studies on Experimental Hypertension : I. The Production of Persistent Elevation of Systolic Blood Pressure by Means of Renal Ischemia
. J Exp Med
. 1934
Feb
;59
(3
):347
–79
.
[PubMed]
0022-10078.
Wiesel
P
, Mazzolai
L
, Nussberger
J
, Pedrazzini
T
. Two-kidney, one clip and one-kidney, one clip hypertension in mice
. Hypertension
. 1997
Apr
;29
(4
):1025
–30
.
[PubMed]
0194-911X9.
Leenen
FH
, de Jong
W
. A solid silver clip for induction of predictable levels of renal hypertension in the rat
. J Appl Physiol
. 1971
Jul
;31
(1
):142
–4
.
[PubMed]
0021-898710.
Chobanian
AV
, Lichtenstein
AH
, Nilakhe
V
, Haudenschild
CC
, Drago
R
, Nickerson
C
. Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit
. Hypertension
. 1989
Aug
;14
(2
):203
–9
.
[PubMed]
0194-911X11.
Lerman
LO
, Chade
AR
, Sica
V
, Napoli
C
. Animal models of hypertension: an overview
. J Lab Clin Med
. 2005
Sep
;146
(3
):160
–73
.
[PubMed]
0022-214312.
Daugherty
A
, Manning
MW
, Cassis
LA
. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice
. J Clin Invest
. 2000
Jun
;105
(11
):1605
–12
.
[PubMed]
0021-973813.
Fan
J
, Chen
Y
, Yan
H
, Niimi
M
, Wang
Y
, Liang
J
. Principles and Applications of Rabbit Models for Atherosclerosis Research
. J Atheroscler Thromb
. 2018
Mar
;25
(3
):213
–20
.
[PubMed]
1340-347814.
Fan
J
, Kitajima
S
, Watanabe
T
, Xu
J
, Zhang
J
, Liu
E
, et al Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine
. Pharmacol Ther
. 2015
Feb
;146
:104
–19
.
[PubMed]
0163-725815.
Chobanian
AV
, Haudenschild
CC
, Nickerson
C
, Drago
R
. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit
. Hypertension
. 1990
Mar
;15
(3
):327
–31
.
[PubMed]
0194-911X16.
Waqar
AB
, Koike
T
, Yu
Y
, Inoue
T
, Aoki
T
, Liu
E
, et al High-fat diet without excess calories induces metabolic disorders and enhances atherosclerosis in rabbits
. Atherosclerosis
. 2010
Nov
;213
(1
):148
–55
.
[PubMed]
0021-915017.
Li
S
, Wang
YN
, Niimi
M
, Ning
B
, Chen
Y
, Kang
D
, et al Angiotensin II Destabilizes Coronary Plaques in Watanabe Heritable Hyperlipidemic Rabbits
. Arterioscler Thromb Vasc Biol
. 2016
May
;36
(5
):810
–6
.
[PubMed]
1079-564218.
Wang
C
, Nishijima
K
, Kitajima
S
, Niimi
M
, Yan
H
, Chen
Y
, et al Increased Hepatic Expression of Endothelial Lipase Inhibits Cholesterol Diet-Induced Hypercholesterolemia and Atherosclerosis in Transgenic Rabbits
. Arterioscler Thromb Vasc Biol
. 2017
Jul
;37
(7
):1282
–9
.
[PubMed]
1079-564219.
Koike
T
, Liang
J
, Wang
X
, Ichikawa
T
, Shiomi
M
, Sun
H
, et al Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase
. Cardiovasc Res
. 2005
Feb
;65
(2
):524
–34
.
[PubMed]
0008-636320.
Stary
HC
, Chandler
AB
, Dinsmore
RE
, Fuster
V
, Glagov
S
, Insull
W
Jr, et al A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association
. Circulation
. 1995
Sep
;92
(5
):1355
–74
.
[PubMed]
0009-732221.
Pick
R
, Johnson
PJ
, Glick
G
. Deleterious effects of hypertension on the development of aortic and coronary atherosclerosis in stumptail macaques (Macaca speciosa) on an atherogenic diet
. Circ Res
. 1974
Sep
;35
(3
):472
–82
.
[PubMed]
0009-733022.
Koletsky
S
, Roland
C
, Rivera-Velez
JM
. Rapid acceleration of atherosclerosis in hypertensive rats on high fat diet
. Exp Mol Pathol
. 1968
Dec
;9
(3
):322
–38
.
[PubMed]
0014-480023.
Heptinstall
RH
, Barkley
H
, Porter
KA
. The relative roles of blood cholesterol level and blood pressure level in the production of experimental aortic atheroma in rabbits
. Angiology
. 1958
Apr
;9
(2
):84
–7
.
[PubMed]
0003-319724.
Arruda
RM
, Peotta
VA
, Meyrelles
SS
, Vasquez
EC
. Evaluation of vascular function in apolipoprotein E knockout mice with angiotensin-dependent renovascular hypertension
. Hypertension
. 2005
Oct
;46
(4
):932
–6
.
[PubMed]
0194-911X25.
Nogueira
BV
, Peotta
VA
, Meyrelles
SS
, Vasquez
EC
. Evaluation of aortic remodeling in apolipoprotein E-deficient mice and renovascular hypertensive mice
. Arch Med Res
. 2007
Nov
;38
(8
):816
–21
.
[PubMed]
0188-440926.
Weiss
D
, Kools
JJ
, Taylor
WR
. Angiotensin II-induced hypertension accelerates the development of atherosclerosis in apoE-deficient mice
. Circulation
. 2001
Jan
;103
(3
):448
–54
.
[PubMed]
0009-732227.
Taylor
CL
, Yuan
Z
, Selman
WR
, Ratcheson
RA
, Rimm
AA
. Cerebral arterial aneurysm formation and rupture in 20,767 elderly patients: hypertension and other risk factors
. J Neurosurg
. 1995
Nov
;83
(5
):812
–9
.
[PubMed]
0022-308528.
Mitra
S
, Goyal
T
, Mehta
JL
. Oxidized LDL, LOX-1 and atherosclerosis
. Cardiovasc Drugs Ther
. 2011
Oct
;25
(5
):419
–29
.
[PubMed]
0920-320629.
Park
YM
, Febbraio
M
, Silverstein
RL
. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima
. J Clin Invest
. 2009
Jan
;119
(1
):136
–45
.
[PubMed]
0021-973830.
Ning
B
, Chen
Y
, Waqar
AB
, Yan
H
, Shiomi
M
, Zhang
J
, et al Hypertension enhances advanced atherosclerosis and induces cardiac death in Watanabe heritable hyperlipidemic rabbits
. Am J Pathol
. 2018
Dec
;188
(12
):2936
–47
.
[PubMed]
0002-944031.
Preston
RA
, Jy
W
, Jimenez
JJ
, Mauro
LM
, Horstman
LL
, Valle
M
, et al Effects of severe hypertension on endothelial and platelet microparticles
. Hypertension
. 2003
Feb
;41
(2
):211
–7
.
[PubMed]
0194-911X32.
Franck
G
, Mawson
T
, Sausen
G
, Salinas
M
, Masson
GS
, Cole
A
, et al Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion
. Circ Res
. 2017
Jun
;121
(1
):31
–42
.
[PubMed]
0009-733033.
Chapman
MJ
, Sposito
AC
. Hypertension and dyslipidaemia in obesity and insulin resistance: pathophysiology, impact on atherosclerotic disease and pharmacotherapy
. Pharmacol Ther
. 2008
Mar
;117
(3
):354
–73
.
[PubMed]
0163-725834.
Sarzani
R
, Brecher
P
, Chobanian
AV
. Growth factor expression in aorta of normotensive and hypertensive rats
. J Clin Invest
. 1989
Apr
;83
(4
):1404
–8
.
[PubMed]
0021-973835.
Doran
AC
, Meller
N
, McNamara
CA
. Role of smooth muscle cells in the initiation and early progression of atherosclerosis
. Arterioscler Thromb Vasc Biol
. 2008
May
;28
(5
):812
–9
.
[PubMed]
1079-564236.
Hein
S
, Arnon
E
, Kostin
S
, Schönburg
M
, Elsässer
A
, Polyakova
V
, et al Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms
. Circulation
. 2003
Feb
;107
(7
):984
–91
.
[PubMed]
0009-732237.
Frey
N
, Katus
HA
, Olson
EN
, Hill
JA
. Hypertrophy of the heart: a new therapeutic target?
Circulation
. 2004
Apr
;109
(13
):1580
–9
.
[PubMed]
0009-732238.
Dawber
TR
, Moore
FE
, Mann
GV
. II. Coronary Heart Disease in the Framingham Study
. Int J Epidemiol
. 2015
Dec
;44
(6
):1767
–80
.
[PubMed]
0300-5771© 2019 S. Karger AG, Basel
2019
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
