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Department of Biochemistry, Molecular Biology, and Biophysics University of Minnesota Minneapolis, Minnesota 55455
Address all correspondence and requests for reprints to: Lincoln R. Potter, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Molecular and Cellular Biology Building, 6-155 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455. E-mail: potter{at}umn.edu.
Identifying the primary target tissues and functions of natriuretic peptides has at times proven difficult. For example, the second natriuretic peptide was initially identified in porcine brain extracts (1). Therefore, it was logically named brain natriuretic peptide (BNP). However, subsequent studies indicated that it is present in much higher concentrations in cardiac ventricles (2). Although its role in the brain remains enigmatic, the heart link has been substantially strengthened by two observations. First, serum BNP concentrations are highly correlated with congestive heart failure, an observation that has significant predictive value in the clinic (3), and, secondly, mice lacking BNP develop pressure-induced ventricular fibrosis (4).
The newest member of the family, C-type natriuretic peptide (CNP), also was identified in porcine brain extracts and, like atrial natriuretic peptide (ANP) and BNP, was shown to stimulate urinary sodium and water excretion when injected into rats (5). Subsequent studies suggested the existence of a paracrine vascular natriuretic peptide system in which CNP released from endothelial cells relaxes and inhibits the proliferation of adjacent vascular smooth muscle cells (6). Surprisingly, when the gene for CNP was disrupted in mice, the major phenotype observed was dwarfism, not defects in blood pressure or salt and water handling (7). In fact, C-type "natriuretic" peptide appears to be devoid of natriuretic activity altogether when assayed at physiological concentrations (8, 9). Thus, unlike ANP and BNP, evidence indicating a clear role for CNP in cardiovascular regulation has been slow to emerge. This trend may be changing because a series of papers, including one in this issue of Endocrinology titled "Inhibitory Effect of C-Type Natriuretic Peptide (CNP) on Cultured Cardiac Myocytes Hypertrophy: Interface between CNP and Endothelin-1 Signaling Pathways" (10), are shining new light on the role of CNP in cardiac function.
Perhaps one reason that the effect of CNP on the heart has been underappreciated is that initial reports failed to detect it in this tissue (11). Another reason may be that CNP is barely detectable in serum and, unlike ANP and BNP, serum CNP levels do not increase in response to congestive heart failure. These observations may have initially dissuaded cardiac researchers from investigating the potential interplay between CNP and known cardioregulatory peptides. However, Tokudome et al. (10) have now shown that CNP inhibits the hypertrophy of cardiomyocytes. In addition, a recent article in Circulation (12) reports that CNP levels are elevated in the hearts of patients with congestive heart failure. These studies indicate that CNP is not only in the heart, but that it is also elevated during heart failure and may elicit important compensatory physiological consequences.
Tokudome et al. (10) were very thorough in their analysis of the effects of CNP on cardiac myocytes. They found that CNP attenuated both basal and endothelin-dependent protein expression, ANP secretion (a hallmark of the cardiac hypertrophic response), and the binding activities of the important cardiac transcription factors, GATA-4 and MEF-2. Additionally, they observed that CNP treatment inhibited calcium/calmodulin-dependent kinase and ERK activities as well as endothelin-dependent increases in intracellular calcium concentrations. CNP increased cGMP concentrations in myocytes, and CNP’s effects were mimicked by a cell-permeable cGMP analog, suggesting that the guanylyl cyclase-linked natriuretic receptor-B, NPR-B, mediates these effects (13). Finally, they demonstrated that exposure of myocytes to endothelin inhibits subsequent CNP-dependent cGMP elevations and that an inhibitor of protein kinase C or an intracellular calcium chelator blocked this response. Together, these data indicate that CNP exerts a broad antiproliferative action on cardiac myocytes, which antagonize the actions of endothelin.
As is often the case with interesting papers, the report by Tokudome et al. (10) elicits more questions than answers. For instance, is the effect of CNP specific for endothelin or is it a general inhibitor of cell proliferation? The observation that mice lacking the ANP receptor display dramatically less cardiac hypertrophy when crossed with animals lacking the type I angiotensin II receptor (14) suggests that CNP and ANP may be general pleiotropic antiproliferative factors. However, this remains to be seen. In addition, what is the mechanism of the antiproliferation response? Does it require inhibition of the MAPK pathway? If so, how? Also, if CNP exerts a significant effect on cardiac function, why have no cardiac defects been reported in mice lacking CNP? These and other important questions will likely be tackled in the near future. Answers to these questions will determine whether CNP really should stand for "cardiac natriuretic peptide."
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Received February 11, 2004.
Accepted for publication February 20, 2004.
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  S. J. Nielsen, J. F. Rehfeld, F. Pedersen, J. Kastrup, R. Videbaek, and J. P. Goetze Measurement of Pro-C-Type Natriuretic Peptide in Plasma Clin. Chem., November 1, 2005; 51(11): 2173 - 2176. [Full Text] [PDF]
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 M. Lafontan, C. Moro, C. Sengenes, J. Galitzky, F. Crampes, and M. Berlan An Unsuspected Metabolic Role for Atrial Natriuretic Peptides: The Control of Lipolysis, Lipid Mobilization, and Systemic Nonesterified Fatty Acids Levels in Humans Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2032 - 2042. [Abstract] [Full Text] [PDF]
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