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CD-NP (chimeric natriuretic peptide), also known as cenderitide, is a novel natriuretic peptide developed by the Mayo Clinic as a potential treatment for heart failure.[1][2][3] CD-NP is created by the fusion of the 15 amino acid C-terminus of DNP with the full CNP structure[2] both peptide which are endogenous to humans. This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the natriuretic and diuretic properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP.[1][3]

Molecular problem: fibrosis

When faced with pressure overload, the heart attempts to compensate with a number of structural alterations including hypertrophy of cardiomyocytes and increase of extracellular matrix (ECM) proteins.[4][5] Rapid accumulation of ECM proteins causes excessive fibrosis resulting in decreased myocardial compliance and increased myocardial stiffness.[5][6] The exact mechanisms involved in excessive fibrosis are not fully understood but there is evidence that supports involvement from local growth factors FGF-2, TGF-beta and platelet-derived growth factor.[7][8][9] TGF-β1 plays an important role in cardiac remodelling through the stimulation of fibroblast proliferation, ECM deposition and myocyte hypertrophy.[10][11][12] The increase in TGF-beta 1 expression in a pressure-overloaded heart correlates with the degree of fibrosis, suggesting TGF-beta 1 involvement in the progression from a compensated hypertrophy to failure.[13][14] Through an autocrine mechanism, TGF-beta 1 acts on fibroblasts by binding TGF-beta 1 receptors 1 and 2. Upon receptor activation, the receptor-associated transcription factor Smad becomes phosphorylated and associates with Co-Smad.[15] This newly formed Smad-Co-Smad complex enters the nucleus where it acts as a transcription factor modulating gene expression.[15] Cardiac remodelling of the ECM is also regulated by the CNP/NPR-B pathway as demonstrated by the improved outcomes in transgenic mice with CNP over-expression subjected to myocardial infarction.[16][17] Binding of CNP to NPR-B catalyzes the synthesis of cGMP, which is responsible for mediating the anti-fibrotic effects of CNP.[18] Fibrotic heart tissue is associated with an increase risk of ventricular dysfunction which can ultimately lead to heart failure.[5][19] Thus, anti-fibrotic strategies are a promising approach in the prevention and treatment of heart failure.

Molecular mechanism

As CD-NP interacts with both NRP-A and NRP-B, this drug has antifibrotic potential.[1] Binding of CD-NP to NRP-B elicits an antifibrotic response by catalyzing formation of cGMP similar to the response seen with endogenous CNP. Additionally, in vitro study of human fibroblasts demonstrates that CD-NP reduces TGF-beta 1 induced collagen production.[1][20] These two proposed mechanisms illustrate therapeutic potential for the reduction of fibrotic remodelling in the hypertensive heart. Through combined effects of CNP and DNP, CD-NP treatment results in a reduction in stress on the heart (through natriuresis/diuresis) and inhibition of pro-fibrotic, remodelling pathways.[1]

References

  1. ^ a b c d e McKie et al. (2010) "CD-NP: An innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease." Curr Heart Fail Rep. 7:93-99
  2. ^ a b Lisy et al. (2008) "Design, synthesis and actions of a novel chimeric natriuretic peptide: CD-NP." J Am Coll Cardiol 52:60-68
  3. ^ a b Dickey et al. (2008)"Novel bifuncitonal natriuretic peptides as potential therapeutics." J Biol Chem 283:35003-35009
  4. ^ Bonnin et al (1981) "Collagen synthesis and content in right ventricular hypertrophy in the dog." Am J Physiol 10:703-13
  5. ^ a b c Averil et al. (1976) Cardiac performance in rats with renal hypertension" Circ Res 38:280-288
  6. ^ Weber et al. (1989)"Cardiac interstitium in health and disease" JACC 13:1637-1652
  7. ^ Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardio Res 2001; 89:265-272
  8. ^ Weber KT, Swamynathan, SK, Guntaka, RV, and Sun Y. Angiotensin II and extracellular matrix homeostasis. Int J Biochem Cell Biol 1999. 31:395–403
  9. ^ Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA. 2005. Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc. Natl. Acad. Sci. U. S. A. 102:437–442
  10. ^ Villarreal FJ, Lee AA, Dillmann WH, Giordano FJ. Adenovirusmediated overexpression of human transforming growth factor-beta 1 in rat cardiac fibroblasts, myocytes and smooth muscle cells. J Mol Cell Cardiol 1996; 28:735-742
  11. ^ Eghbali M, Tomek R, Sukhatme VP, Woods C, Bhambi B. Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts: regulation of fibrillar collagen mRNAs and expression of early transcription factors. Circ Res 1991; 69:483-490
  12. ^ Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 3:349-363
  13. ^ Boluyt MO, O’Neill L, Meredith AL, Binf OH, Brooks WW, Conrad CH, Crow MT, Lakatta EG. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Circ Res 1994; 75:23-32
  14. ^ Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V, Bauer EP, Klovekorn WP, Schaper J. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structure deterioration and compensatory mechanisms. Circ 2003; 107:984-991
  15. ^ a b Chen YG, Hata A, Lo RS. Determinants of specificity in TGF-β signal transduction. Genes Dev 1998; 12:2144-2152
  16. ^ Wang Y, de Waard MC, Sterner-Kock A, Stepan H, Schultheiss HP, Duncker DJ, Walther T. Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice. Eur J Heart Fail 2007; 548-557
  17. ^ Langenickel TH, buttgereit J, Pagel-Langenickel I, Lindner M, Monti J, Beuerlein K, Al-Saadi N, Plehm R, Popova E, Tank J, Dietz R, Willenbrock R, Bader M. Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B. PNAS 2006; 103:4735-4740
  18. ^ Potter LR, Yoder AR, Flora AR, Antos LK, Dickey DM. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol 2009; 191:341-366
  19. ^ Kenchaiach S, Pfeffer MA. Cardiac remodelling in systemic hypertension. Med Clin North Am 2004; 88:115-130
  20. ^ Ichiki T, Huntley BK, Sangaralingham SJ. A novel designer natriuretic peptide CD-NP suppresses TGF-beta 1 induced collagen type I production in human cardiac fibroblasts. J Card Fail 2009; 15:S34
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