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Commentaries |
From the Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California
The clinical association of hypertension and heart disease has been recognized for more than a century. However, a direct association between hypertension and thrombosis is not apparent. With the introduction of therapeutic interventional coronary artery ballooning and related procedures including introduction of stents, the occurrence of secondary local vasculopathy as well as thrombosis presents a significant threat. The view that hypertension, which is mediated by angiotensin II, is the immediate driving force for the various forms of associated vasculopathy is naive. Angiotensin II is the product of the renin, angiotensinogen, angiotensin-converting enzyme cascade. Recent studies have identified the cellular effects of angiotensin II as highly pleomorphic.1 Apart from the well recognized effects of angiotensin II on local vascular tension, namely vascular smooth muscle contraction, it is now recognized that angiotensin II, via engagement of its cognate endothelial surface receptor AT1, induces biosynthesis and local release of a number of cell modulatory proteins including platelet-derived growth factor, basic fibroblast growth factor, insulin growth factor, transforming growth factor-ß, and undoubtedly other molecules, as well as molecules influencing the thrombogenic pathways, such as plasminogen activator inhibitors.2 The local effects of angiotensin II include local neointimal thickening3 as well as hypertension and cardiac pathology.4 Although most of the pleomorphic cellular products are not directly implicated in the mediation of vasoconstriction and hypertension, indirect effects cannot be entirely excluded.
Available molecular and cellular evidence, coupled with clinical investigations, does not provide an entire map of the molecular pathways associated with angiotensin II effects. The proposition that the effects of hypertension on the coronary artery contributes to atherosclerosis and stenosis remains intact, but hypertension cannot directly account for acute coronary occlusion where an acute thrombotic event is the mechanism. The frequent cause of acute coronary thrombosis and resultant myocardial infarction is now suspected to result directly from the rupture of a susceptible atherosclerotic plaque rich in tissue factor (TF), the major initiating cell surface receptor and cofactor of the thrombogenic cascade.5 Presumably, certain fragile plaques, designated susceptible plaques, are weakened by internal proteolysis of the fibrous cap6 and rendered more susceptible to rupture by the hypertensive flow and pressure.
In this issue of The American
Journal of Pathology,7
Müller and coworkers
provide an important linkage between the molecular pathology of
hypertension and thrombogenic and inflammatory cascades with evidence
that angiotensin II, through its endothelial surface receptor
AT1, induces activation of the nuclear factor-
B (NF-B) system with transcription and expression TF by the
endothelium in vivo in a transgenic model of severe cardiac
vasculopathy. This breaks important ground and may add insight into the
risk profile of essential hypertension. Notably, current convention and
clinical data do not significantly implicate essential hypertension
thrombotic risk, except for pulmonary hypertension; however, this may
need to be reassessed. In the Bruneck study8
there is an
association between atherosclerosis and elevated markers favoring
thrombosis. The work of Dzau,1
as well as others, on the
effects of hypertension, and more significantly of angiotensin II on
vascular pathology, raises issues whether TF expression demonstrated
here by local cells in cardiac tissues may contribute to the pathology.
Angiotensin II might stimulate increased synthesis of TF in some
atherosclerotic plaques and render them more dangerous if they rupture,
thus driving local occlusive thrombosis of the subject coronary artery.
Equally intriguing, however, is the possibility that the thrombogenic
effects of TF are a distraction from other effects that are brought
into play. TF, by initiating the coagulation protease cascade, drives a
number of cellular responses that are mediated by the protease products
that proteolytically activate one or more members of the
protease-activated receptor family of cell surface
receptors,9
the most notable of which, protease-activated
receptor-1, is activated in a quite novel manner by thrombin
and signals the cell.
In the present study,7
Müller et al use an in
vivo model of transgenic rats carrying and overexpressing a murine
renin and a human angiotensinogen gene,4
a state of
affairs that results in an extremely severe form of cardiac
vasculopathy mediated by the product angiotensin II. The life span of
untreated rats is a mere 7 weeks; thus, death is a clearly establish
end point, but not the only one in this carefully executed model of
angiotensin II-mediated vasculopathy. The authors use an
AT1 receptor antagonist to demonstrate
receptor-specific amelioration of disease and extended life span. Using
TF transcription and expression as the indicator, they demonstrate that
AT1 engagement drives activation of activator
protein-1 and NF-B, well known for their regulation of
transcription of a number of inflammatory molecules. It is known that
these regulate TF transcription and expression as well, and this is
observed to be the case with AT1 signaling of the
cells by angiotensin II. In this transgenic rat model, intravascular
microthrombosis has apparently been observed. AT1
blockade by valsartan provides the specificity and pathology control,
and is effective. We are left with questions about the significance of
TF expression. Does it contribute directly to this form of severe
vasculopathy, or is it more of a marker of NF-B activation? Does it
occur in humans in association with essential hypertension? And to what
degree does this transgenic rodent model parallel a subset of severe
angiotensin II-driven hypertensive disease of humans? Nevertheless, the
quality of the observations clearly indicates that there may be a link
between the pathogenic pathways initiated and driven by TF expression,
other NF-B inflammatory molecules, and hypertension associated with
elevations of angiotensin II levels in vivo.
Footnotes
Address reprint requests to Thomas S. Edgington, M.D., Departments of Immunology and Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, C204, La Jolla, CA 92037-1092. E-mail: tse{at}scripps.edu
Accepted for publication May 18, 2000.
References
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