Chemistry:Cenderitide
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Cenderitide (also known as chimeric natriuretic peptide or CD-NP) is a natriuretic peptide developed by the Mayo Clinic as a potential treatment for heart failure.[1][2][3] Cenderitide is created by the fusion of the 15 amino acid C-terminus of the snake venom dendroaspis natriuretic peptide (DNP) with the full C-type natriuretic peptide (CNP) structure.[2] 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 cenderitide interacts with both NRP-A and NRP-B, this drug has antifibrotic potential.[1] Binding of cenderitide 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 cenderitide 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, cenderitide treatment results in a reduction in stress on the heart (through natriuresis/diuresis) and inhibition of pro-fibrotic, remodeling pathways.[1]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 "CD-NP: an innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease". Current Heart Failure Reports 7 (3): 93–9. September 2010. doi:10.1007/s11897-010-0016-6. PMID 20582736.
- ↑ 2.0 2.1 "Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP". Journal of the American College of Cardiology 52 (1): 60–8. July 2008. doi:10.1016/j.jacc.2008.02.077. PMID 18582636.
- ↑ 3.0 3.1 "Novel bifunctional natriuretic peptides as potential therapeutics". The Journal of Biological Chemistry 283 (50): 35003–9. December 2008. doi:10.1074/jbc.M804538200. PMID 18940797.
- ↑ "Collagen synthesis and content in right ventricular hypertrophy in the dog". The American Journal of Physiology 241 (5): H708–13. November 1981. doi:10.1152/ajpheart.1981.241.5.H708. PMID 7304760.
- ↑ 5.0 5.1 5.2 "Cardiac performance in rats with renal hypertension". Circulation Research 38 (4): 280–8. April 1976. doi:10.1161/01.res.38.4.280. PMID 131007.
- ↑ "Cardiac interstitium in health and disease: the fibrillar collagen network.". Journal of the American College of Cardiology 13 (7): 1637–52. June 1989. doi:10.1016/0735-1097(89)90360-4. PMID 2656824.
- ↑ "Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart". Cardiovascular Research 89 (2): 265–72. February 2011. doi:10.1093/cvr/cvq308. PMID 20880837.
- ↑ "Angiotensin II and extracellular matrix homeostasis". The International Journal of Biochemistry & Cell Biology 31 (3–4): 395–403. 1999. doi:10.1016/s1357-2725(98)00125-3. PMID 10224666.
- ↑ "Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase". Proceedings of the National Academy of Sciences of the United States of America 102 (2): 437–42. January 2005. doi:10.1073/pnas.0408704102. PMID 15625103. Bibcode: 2005PNAS..102..437S.
- ↑ "Adenovirus-mediated overexpression of human transforming growth factor-beta 1 in rat cardiac fibroblasts, myocytes and smooth muscle cells". Journal of Molecular and Cellular Cardiology 28 (4): 735–42. April 1996. doi:10.1006/jmcc.1996.0068. PMID 8732501.
- ↑ "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". Circulation Research 69 (2): 483–90. August 1991. doi:10.1161/01.res.69.2.483. PMID 1860186.
- ↑ "Myofibroblasts and mechano-regulation of connective tissue remodelling". Nature Reviews. Molecular Cell Biology 3 (5): 349–63. May 2002. doi:10.1038/nrm809. PMID 11988769.
- ↑ "Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components". Circulation Research 75 (1): 23–32. July 1994. doi:10.1161/01.res.75.1.23. PMID 8013079.
- ↑ "Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms". Circulation 107 (7): 984–91. February 2003. doi:10.1161/01.cir.0000051865.66123.b7. PMID 12600911.
- ↑ 15.0 15.1 "Determinants of specificity in TGF-beta signal transduction". Genes & Development 12 (14): 2144–52. July 1998. doi:10.1101/gad.12.14.2144. PMID 9679059.
- ↑ "Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice". European Journal of Heart Failure 9 (6–7): 548–57. 2007. doi:10.1016/j.ejheart.2007.02.006. PMID 17407830.
- ↑ "Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B". Proceedings of the National Academy of Sciences of the United States of America 103 (12): 4735–40. March 2006. doi:10.1073/pnas.0510019103. PMID 16537417. Bibcode: 2006PNAS..103.4735L.
- ↑ "Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications". CGMP: Generators, Effectors and Therapeutic Implications. Handbook of Experimental Pharmacology. 191. 2009. pp. 341–66. doi:10.1007/978-3-540-68964-5_15. ISBN 978-3-540-68960-7.
- ↑ "Cardiac remodeling in systemic hypertension". The Medical Clinics of North America 88 (1): 115–30. January 2004. doi:10.1016/s0025-7125(03)00168-8. PMID 14871054.
- ↑ "A novel designer natriuretic peptide CD-NP suppresses TGF-beta 1 induced collagen type I production in human cardiac fibroblasts.". Journal of Cardiac Failure 15 (6 supplement): S34. 2009. doi:10.1016/j.cardfail.2009.06.318.
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