Abstract
B-type natriuretic peptide (BNP) decreases cardiac preload and hypertrophy. As such, synthetic BNP, nesiritide, was approved for the treatment of acutely decompensated heart failure. However, two problems limit its therapeutic potential. First, ensuing hypertension decreases urine output, and second, guanylyl cyclase-A (GC-A), the primary signaling receptor for BNP, is down-regulated in heart failure. Thus, alternative or chimeric natriuretic peptides maintaining the renal but lacking the vasorelaxation properties of BNP provide an alternative approach. Here, we examined the ability of single amino acid substitutions in the conserved 17-amino acid disulfide ring structure of human BNP to activate GC-A and guanylyl cyclase-B (GC-B), which is not reduced in heart failure. We hypothesized that substitution of highly conserved residues in BNP with highly conserved residues from a GC-B-specific peptide would yield BNP variants with increased and decreased potency for human GC-B and GC-A, respectively. Substitution of Leu for Arg13 (l-bnp) yielded a 5-fold more potent activator of GC-B and 7-fold less potent activator of GC-A compared with wild type. l-bnp also bound GC-A 4.5-fold less tightly than wild type. In contrast, substitution of Met for Ser21 (M-BNP) had no effect. A peptide containing both the Leu and Met substitutions behaved similarly to l-bnp. Meanwhile, wild-type and l-bnp bound the natriuretic peptide clearance receptor with similar affinities. These data indicate that Arg13 of BNP is a critical discriminator of binding to guanylyl cyclase-linked but not clearance natriuretic peptide receptors, supporting designer natriuretic peptides as an alternative to wild-type BNP for the treatment of heart failure.
Footnotes
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R21-HL093402]; the American Heart Association [Grant 0950053G]; and the Minnesota Medical Foundation.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.066084.
-
ABBREVIATIONS:
- ANP
- atrial natriuretic peptide
- BNP
- B-type natriuretic peptide
- CNP
- C-type natriuretic peptide
- M-BNP
- Met-BNP
- l-bnp
- leu-BNP
- LM-BNP
- Leu-Met-BNP
- GC-A
- guanylyl cyclase-A
- GC-B
- guanylyl cyclase-B
- NPR-C
- natriuretic peptide receptor C
- wt
- wild type.
- Received May 6, 2010.
- Accepted June 8, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|