LETTER TO THE EDITOR
C-type natriuretic peptide and vascular remodeling: Reply
Hiroaki Shimokawa, MDa,
Kunio Morishige, MDa and
Akira Takeshita, MDa
a Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
shimo{at}cardiol.med.kyushu-u.ac.jp
We are grateful for the opportunity to respond to the valuable comments by Drs. Davidson and Struthers concerning our recent article in the Journal (1). In our article, we showed that adenovirus-mediated overexpression of C-type natriuretic peptide (CNP) in the porcine coronary artery suppresses vascular constrictive remodeling after balloon injury in vivo. However, as the authors pointed out, we did not mention the possible effect of CNP on the renin-angiotensin-aldosterone system, mainly because we did not specifically examine this system in our study.
It is indeed possible that CNP/cGMP cascade may suppress the vascular remodeling through various mechanisms, including smooth muscle relaxation and inhibition of proliferation and migration of smooth muscle cells and subsequent extracellular matrix deposition. Vascular remodeling appears to be caused by complicated processes, in which the renin-angiotensin-aldosterone system is involved. In this sense, we fully agree with Drs. Davidson and Struthers that CNP should be regarded as an endogenous regulator of the vascular renin-angiotensin-aldosterone system (2). In our porcine model of inflammatory coronary arteriosclerosis, which is characterized by constrictive remodeling and neointimal formation, a complex cytokine network appears to be involved, including several growth factors and inflammatory cytokines (3). Furthermore, recent studies suggested that other mechanisms, such as endothelial dysfunction, collagen accumulation, and matrix-metalloproteinase activity, may also be involved in the pathogenesis of vascular remodeling (4,5). We have recently demonstrated that small GTP binding protein Rho and its target Rho-kinase play an important role in the molecular mechanism of vascular hyperreactivity as well as vascular remodeling in our porcine model (6,7). Importantly, the Rho/Rho-kinase pathway is involved in the cardiovascular effects of angiotensin II (8).
Taken together, it is highly possible in our study that the inhibitory effect of CNP on the development of vascular remodeling was mediated, at least in part, by its modulatory effect on the vascular renin-angiotensin-aldoesterone system. However, it remains to be examined whether adenovirus-mediated overexpression of CNP in the coronary artery actually reduces the local production of angiotensin II in our porcine model in vivo.
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References
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1. Morishige K, Shimokawa H, Yamawaki T, et al. Local adenovirus-mediated transfer of C-type natriuretic peptide suppresses vascular remodeling in porcine coronary arteries in vivo. J Am Coll Cardiol. 2000;35:1040–1047[Abstract/Free Full Text]
2. Davidson NC, Barr CS, Struthers AD. C-type natriuretic peptide. An endogenous inhibitor of vascular angiotensin-converting enzyme activity. Circulation. 1996;93:1155–1159[Abstract/Free Full Text]
3. Shimokawa H, Ito A, Fukumoto Y, et al. Chronic treatment with interleukin-1ß induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J Clin Invest. 1996;97:769–776[Medline]
4. Lafont A, Durand E, Samuel JL, et al. Endothelial dysfunction and collagen accumulation: two independent factors for restenosis and constrictive remodeling after experimental angioplasty. Circulation. 1999;100:1109–1115[Abstract/Free Full Text]
5. de Smet BJ, de Kleijn D, Hanemaaijer R, et al. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig. Circulation. 2000;101:2962–2967[Abstract/Free Full Text]
6. Kandabashi T, Shimokawa H, Miyata K, et al. Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1ß. Circulation. 2000;101:1319–1323[Abstract/Free Full Text]
7. Morishige K, Shimokawa H, Eto Y, et al. Local adenovirus-mediated transfer of dominant-negative Rho-kinase induces a regression of coronary remodeling in a swine model with interleukin-1ß. (abstr)J Mol Coll Cardiol. 1999;31:A167[CrossRef]
8. Yamakawa T, Tanaka S, Numaguchi K, et al. Involvement of Rho-kinase in angiotensin II-induced hypertophy of rat vascular smooth muscle cells. Hypertension. 2000;35:313–318[Abstract/Free Full Text]
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