AORTIC STENOSIS
Induction of local angiotensin II-producing systems in stenotic aortic valves
Satu Helske, MD*,
Ken A. Lindstedt, PhD*,
Mika Laine, MD, PhD ,
Mikko Mäyränpää, MD*,
Kalervo Werkkala, MD, PhD ,
Jyri Lommi, MD, PhD ,
Heikki Turto, MD, PhD,
Markku Kupari, MD, PhD and
Petri T. Kovanen, MD, PhD*,*
* Wihuri Research Institute, Helsinki, Finland
Minerva Institute for Medical Research, Helsinki, Finland
Divisions of Cardiothoracic Surgery
Cardiology, Helsinki University Central Hospital, Helsinki, Finland
Manuscript received May 26, 2004;
revised manuscript received July 6, 2004,
accepted July 28, 2004.
* Reprint requests and correspondence: Dr. Petri T. Kovanen, Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland (Email: petri.kovanen{at}wri.fi).
OBJECTIVES: The purpose of this study was to investigate the expression of angiotensin II (Ang II)-producing enzyme systems in normal and stenotic aortic valves.
BACKGROUND: Chronic inflammation and fibrosis are involved in the pathogenesis of aortic stenosis (AS), but the detailed molecular mechanisms of this atherosclerosis-like process remain obscure. Angiotensin II, a powerful mediator of inflammation and fibrosis, may participate in AS progression.
METHODS: Stenotic aortic valves (n = 86) were obtained from patients undergoing valve replacement surgery, and control valves (n = 11) were obtained from patients undergoing cardiac transplantation. Angiotensin-converting enzyme (ACE) and mast cell (MC)-derived chymase were quantified by reverse-transcription polymerase chain reaction, autoradiography, and immunostaining. The MCs, macrophages, and T lymphocytes were detected by immunohistochemistry, and angiotensin II type 1 receptor (AT-1R) by autoradiography.
RESULTS: Compared with control valves, stenotic aortic valves showed a significant increase in both messenger ribonucleic acid (mRNA) (p = 0.001) and protein (p < 0.001) expression of ACE, which colocalized with macrophages. Similarly, the expression of AT-1R protein and chymase mRNA and proteinwas upregulated (p < 0.001), and the number of MCs was six-fold higher in stenotic than in normal valves. The MCs were associated with the calcified areas, and—in contrast to control valves—showed an increased degree of degranulation, a prerequisite for chymase secretion and action.
CONCLUSIONS: Angiotensin-converting enzyme and chymase, two Ang II-forming enzymes, are locally expressed in aortic valves, and owing to infiltration of macrophages and MCs, are further upregulated in stenotic valves. These novel findings, implicating chronic inflammation and an increased expression of local Ang II-forming systems, suggest that therapeutic interventions aiming at inhibiting these processes may slow AS progression.
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Abbreviations and Acronyms
| | ACE = angiotensin-converting enzyme | | Ang II = angiotensin II | | AS = aortic stenosis | | AT-1R = angiotensin II type 1 receptor | | AT-2R = angiotensin II type 2 receptor | | DNA = deoxyribonucleic acid | | GAPDH = glyceraldehyde-3-phosphate dehydrogenase | | LDL = low-density lipoprotein | | MC = mast cell | | mRNA = messenger ribonucleic acid | | RT-PCR = reverse transcription-polymerase chain reaction |
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