Could angiotensin receptor blockers and activation of AT2 induce plaque rupture, rather than repair?
I read with interest the editorial by Verma and Strauss on the report
of Angiotensin receptor blockers (ARBs) and myocardial infarction (MI). 1
An acknowledged preliminary look at an important topic. The authors
pointed out that the ARBs increase the rates of MI in some trials despite
their beneficial effects on reducing blood pressure. Unfortunately there
is no careful explanation of the mechanisms involved. I speculate that
long-term administration of ARBs results in a possible overstimulation of
angiotensin II (Ang II) type 2 receptors (AT2) and thus a antifibrotic
effects of such stimulation. Maybe this could lead to a thin, friable
fibrous cap with a reduced collagen and vascular smooth muscle cells
(VSMCs) content, what is a characteristic feature of atherosclerotic
plaques that are vulnerable to rupture.
AT2 is present in the vasculature in adults and is believed to induce
vasodilation and antigrowth and antihypertrophic effects. 2 In accordance
with this finding, treatment of mice with valsartan significantly
decreased neointima formation and the proliferation of VSMCs.3 Also,
stimulation of AT2 by Ang II has been shown to enhance apoptosis in aortic
smooth muscle cells. 4 In addition, it was shown that activation of AT2
could induce vascular cell apoptosis and thus participate in the early
phase of vascular remodeling in rats subjected to chronic AT1 blockade
with losartan.5 Finally, slowed proliferation of intimal VSMCs is further
feature of advanced atherosclerosis that promote plaque instability and
rupture, rather than repair. 6
However, the ability of Ang II to mediate apoptosis in vascular
smooth muscle cells may depend on the cell phenotype, and it is therefore
difficult to predict the effects in human beings of long-term
overstimulation of AT2 resulting from ARB therapy. This information has to
be gathered from the results of future studies in real patients.
1.Verma S, Strauss M. Angiotensin receptor blockers and myocardial
infarction. BMJ 2004;329:1249–50
2.Horiuchi M, Akishita M, Dzau VJ. Recent progress in angiotensin II type
2 receptor research in the cardiovascular system. Hypertension. 1999; 33:
613–621.
3.Wu L, Iwai M,Nakagami H et al. Roles of Angiotensin II Type 2 Receptor
Stimulation Associated With Selective Angiotensin II Type 1 Receptor
Blockade With Valsartan in the Improvement of Inflammation-Induced
Vascular Injury.Circulation. 2001;104:2716
4.Diep QN, Li JS, Schiffrin EL, et al. In vivo study of AT1 and AT2
angiotensin receptors in apoptosis in rat blood vessels. Hypertension.
1999; 34: 617–624.
5.Marchand EL, Der Sarkissian S, Hamet P, et al. Caspase-dependent cell
death mediates the early phase of aortic hypertrophy regression in
losartan-treated spontaneously hypertensive rats. Circ Res. 2003; 92:
777–784.
6.Bennett MR, Macdonald K, Chan S et al. Cooperative interactions between
RB and p53 regulate cell proliferation, cell senescence, and apoptosis in
human vascular smooth muscle cells from atherosclerotic plaques. Circ Res
1998; 82: 704–712.
Competing interests:
None declared
Competing interests:
No competing interests
23 December 2004
Luciano J Vacanti
Supervisory cardiologist
Heart Institute (InCor), Zerbini Foundation, Brasilia, Brazil
Rapid Response:
Could angiotensin receptor blockers and activation of AT2 induce plaque rupture, rather than repair?
I read with interest the editorial by Verma and Strauss on the report
of Angiotensin receptor blockers (ARBs) and myocardial infarction (MI). 1
An acknowledged preliminary look at an important topic. The authors
pointed out that the ARBs increase the rates of MI in some trials despite
their beneficial effects on reducing blood pressure. Unfortunately there
is no careful explanation of the mechanisms involved. I speculate that
long-term administration of ARBs results in a possible overstimulation of
angiotensin II (Ang II) type 2 receptors (AT2) and thus a antifibrotic
effects of such stimulation. Maybe this could lead to a thin, friable
fibrous cap with a reduced collagen and vascular smooth muscle cells
(VSMCs) content, what is a characteristic feature of atherosclerotic
plaques that are vulnerable to rupture.
AT2 is present in the vasculature in adults and is believed to induce
vasodilation and antigrowth and antihypertrophic effects. 2 In accordance
with this finding, treatment of mice with valsartan significantly
decreased neointima formation and the proliferation of VSMCs.3 Also,
stimulation of AT2 by Ang II has been shown to enhance apoptosis in aortic
smooth muscle cells. 4 In addition, it was shown that activation of AT2
could induce vascular cell apoptosis and thus participate in the early
phase of vascular remodeling in rats subjected to chronic AT1 blockade
with losartan.5 Finally, slowed proliferation of intimal VSMCs is further
feature of advanced atherosclerosis that promote plaque instability and
rupture, rather than repair. 6
However, the ability of Ang II to mediate apoptosis in vascular
smooth muscle cells may depend on the cell phenotype, and it is therefore
difficult to predict the effects in human beings of long-term
overstimulation of AT2 resulting from ARB therapy. This information has to
be gathered from the results of future studies in real patients.
1.Verma S, Strauss M. Angiotensin receptor blockers and myocardial
infarction. BMJ 2004;329:1249–50
2.Horiuchi M, Akishita M, Dzau VJ. Recent progress in angiotensin II type
2 receptor research in the cardiovascular system. Hypertension. 1999; 33:
613–621.
3.Wu L, Iwai M,Nakagami H et al. Roles of Angiotensin II Type 2 Receptor
Stimulation Associated With Selective Angiotensin II Type 1 Receptor
Blockade With Valsartan in the Improvement of Inflammation-Induced
Vascular Injury.Circulation. 2001;104:2716
4.Diep QN, Li JS, Schiffrin EL, et al. In vivo study of AT1 and AT2
angiotensin receptors in apoptosis in rat blood vessels. Hypertension.
1999; 34: 617–624.
5.Marchand EL, Der Sarkissian S, Hamet P, et al. Caspase-dependent cell
death mediates the early phase of aortic hypertrophy regression in
losartan-treated spontaneously hypertensive rats. Circ Res. 2003; 92:
777–784.
6.Bennett MR, Macdonald K, Chan S et al. Cooperative interactions between
RB and p53 regulate cell proliferation, cell senescence, and apoptosis in
human vascular smooth muscle cells from atherosclerotic plaques. Circ Res
1998; 82: 704–712.
Competing interests:
None declared
Competing interests: No competing interests