Cenderitide

Last updated
Cenderitide
Legal status
Legal status
  • Investigational
Identifiers
  • glycyl-L-leucyl-L-seryl-L-lysylglycyl-L-cysteinyl-L-phenylalanylglycyl-L-leucyl-L-lysyl-L-leucyl-L-α-aspartyl-L-arginyl-L-isoleucylglycyl-L-seryl-L-methionyl-L-serylglycyl-L-leucylglycyl-L-cysteinyl-L-prolyl-L-seryl-L-leucyl-L-arginyl-L-α-aspartyl-L-prolyl-L-arginyl-L-prolyl-L-asparaginyl-L-alanyl-L-prolyl-L-seryl-L-threonyl-L-seryl-L-alanine, cyclic (6→22)-disulfide
CAS Number
DrugBank
UNII

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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Atrial natriuretic peptide</span> Cardiac hormone which increases renal sodium excretion

Atrial natriuretic peptide (ANP) or atrial natriuretic factor (ANF) is a natriuretic peptide hormone secreted from the cardiac atria that in humans is encoded by the NPPA gene. Natriuretic peptides are a family of hormone/paracrine factors that are structurally related. The main function of ANP is causing a reduction in expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized and secreted by cardiac muscle cells in the walls of the atria in the heart. These cells contain volume receptors which respond to increased stretching of the atrial wall due to increased atrial blood volume.

<span class="mw-page-title-main">Fibrosis</span> Excess connective tissue in healing

Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue.

In cardiology, ventricular remodeling refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise or after injury to the heart muscle. The injury is typically due to acute myocardial infarction, but may be from a number of causes that result in increased pressure or volume, causing pressure overload or volume overload on the heart. Chronic hypertension, congenital heart disease with intracardiac shunting, and valvular heart disease may also lead to remodeling. After the insult occurs, a series of histopathological and structural changes occur in the left ventricular myocardium that lead to progressive decline in left ventricular performance. Ultimately, ventricular remodeling may result in diminished contractile (systolic) function and reduced stroke volume.

<span class="mw-page-title-main">Transforming growth factor beta</span> Cytokine

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.

Adenosine A<sub>1</sub> receptor Cell surface receptor found in humans

The adenosine A1 receptor (A1AR) is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.

<span class="mw-page-title-main">Myofibroblast</span>

A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.

Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic cardiac muscle is stiffer and less compliant and is seen in the progression to heart failure. The description below focuses on a specific mechanism of valvular pathology but there are other causes of valve pathology and fibrosis of the cardiac muscle.

<span class="mw-page-title-main">Natriuretic peptide</span>

A natriuretic peptide is a hormone molecule that plays a crucial role in the regulation of the cardiovascular system. These hormones were first discovered in the 1980s and were found to have very strong diuretic, natriuretic, and vasodilatory effects. There are three main types of natriuretic peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Two minor hormones include Urodilatin (URO) which is processed in the kidney and encoded by the same gene as ANP, and Dendroaspis NP (DNP) that was discovered through isolation of the venom from the green mamba snake. Since they are activated during heart failure, they are important for the protection of the heart and its tissues.

TRPC is a family of transient receptor potential cation channels in animals.

The ST2 cardiac biomarker is a protein biomarker of cardiac stress encoded by the IL1RL1 gene. ST2 signals the presence and severity of adverse cardiac remodeling and tissue fibrosis, which occurs in response to myocardial infarction, acute coronary syndrome, or worsening heart failure.

<span class="mw-page-title-main">Dermatopontin</span> Protein-coding gene in the species Homo sapiens

Dermatopontin also known as tyrosine-rich acidic matrix protein (TRAMP) is a protein that in humans is encoded by the DPT gene. Dermatopontin is a 22-kDa protein of the noncollagenous extracellular matrix (ECM) estimated to comprise 12 mg/kg of wet dermis weight. To date, homologues have been identified in five different mammals and 12 different invertebrates with multiple functions. In vertebrates, the primary function of dermatopontin is a structural component of the ECM, cell adhesion, modulation of TGF-β activity and cellular quiescence). It also has pathological involvement in heart attacks and decreased expression in leiomyoma and fibrosis. In invertebrate, dermatopontin homologue plays a role in hemagglutination, cell-cell aggregation, and expression during parasite infection.

<span class="mw-page-title-main">Diabetic cardiomyopathy</span> Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure(HF), with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

Pancreatic stellate cells (PaSCs) are classified as myofibroblast-like cells that are located in exocrine regions of the pancreas. PaSCs are mediated by paracrine and autocrine stimuli and share similarities with the hepatic stellate cell. Pancreatic stellate cell activation and expression of matrix molecules constitute the complex process that induces pancreatic fibrosis. Synthesis, deposition, maturation and remodelling of the fibrous connective tissue can be protective, however when persistent it impedes regular pancreatic function.

<span class="mw-page-title-main">Myocardial scarring</span>

Myocardial scarring is the accumulation of fibrous tissue resulting after some form of trauma to the cardiac tissue. Fibrosis is the formation of excess tissue in replacement of necrotic or extensively damaged tissue. Fibrosis in the heart is often hard to detect because fibromas, scar tissue or small tumors formed in one cell line, are often formed. Because they are so small, they can be hard to detect by methods such as magnetic resonance imaging. A cell line is a path of fibrosis that follow only a line of cells.

<span class="mw-page-title-main">Galectin-3</span> Protein-coding gene in the species Homo sapiens

Galectin-3 is a protein that in humans is encoded by the LGALS3 gene. Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified.

<span class="mw-page-title-main">Pirfenidone</span> Chemical compound

Pirfenidone, sold under the brand name Pirespa among others, is a medication used for the treatment of idiopathic pulmonary fibrosis. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II.

<span class="mw-page-title-main">Heart failure with preserved ejection fraction</span> Medical condition

Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the left ventricle is maximally filled – is normal, defined as greater than 50%; this may be measured by echocardiography or cardiac catheterization. Approximately half of people with heart failure have preserved ejection fraction, while the other half have a reduction in ejection fraction, called heart failure with reduced ejection fraction (HFrEF).

<span class="mw-page-title-main">Oxymatrine</span> Chemical compound

Oxymatrine is one of many quinolizidine alkaloid compounds extracted from the root of Sophora flavescens, a Chinese herb. It is very similar in structure to matrine, which has one less oxygen atom. Oxymatrine has a variety of effects in vitro and in animal models, including protection against apoptosis, tumor and fibrotic tissue development, and inflammation. Furthermore, oxymatrine has been shown to decrease cardiac ischemia, myocardial injury, arrhythmias, and improve heart failure by increasing cardiac function.

<span class="mw-page-title-main">Brain natriuretic peptide 32</span> Hormone secreted in the heart

Brain natriuretic peptide 32 (BNP), also known as B-type natriuretic peptide, is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume. BNP is one of the three natriuretic peptides, in addition to ANP and CNP.

<span class="mw-page-title-main">Alamandine</span> Pharmacology of a New Angiotensin Peptide

Alamandine is a member of renin-angiotensin system (RAS) with cardiovascular functions that are protective and opposing to the classical axis. Alamandine is a product of ACE2-dependent catalytic hydrolysis of angiotensin A and can also be generated by decarboxylation of aspartic acid residue of Ang-(1-7). Ang A is Ala1-Ang II. In mononuclear leucocytes, angiotensin II is converted to Ang A by decarboxylation of aspartic acid. Ang A is detected in human circulation and was shown to be higher in individuals with end-stage renal disease.

References

  1. 1 2 3 4 5 McKie PM, Sangaralingham SJ, Burnett JC (September 2010). "CD-NP: an innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease". Current Heart Failure Reports. 7 (3): 93–9. doi:10.1007/s11897-010-0016-6. PMID   20582736. S2CID   23726451.
  2. 1 2 Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett JC (July 2008). "Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP". Journal of the American College of Cardiology. 52 (1): 60–8. doi:10.1016/j.jacc.2008.02.077. PMC   2575424 . PMID   18582636.
  3. 1 2 Dickey DM, Burnett JC, Potter LR (December 2008). "Novel bifunctional natriuretic peptides as potential therapeutics". The Journal of Biological Chemistry. 283 (50): 35003–9. doi: 10.1074/jbc.M804538200 . PMC   3259864 . PMID   18940797.
  4. ↑ Bonnin CM, Sparrow MP, Taylor RR (November 1981). "Collagen synthesis and content in right ventricular hypertrophy in the dog". The American Journal of Physiology. 241 (5): H708–13. doi:10.1152/ajpheart.1981.241.5.H708. PMID   7304760.
  5. 1 2 3 Averill DB, Ferrario CM, Tarazi RC, Sen S, Bajbus R (April 1976). "Cardiac performance in rats with renal hypertension". Circulation Research. 38 (4): 280–8. doi: 10.1161/01.res.38.4.280 . PMID   131007.
  6. ↑ Weber KT (June 1989). "Cardiac interstitium in health and disease: the fibrillar collagen network". Journal of the American College of Cardiology. 13 (7): 1637–52. doi: 10.1016/0735-1097(89)90360-4 . PMID   2656824.
  7. ↑ Creemers EE, Pinto YM (February 2011). "Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart". Cardiovascular Research. 89 (2): 265–72. doi: 10.1093/cvr/cvq308 . PMID   20880837.
  8. ↑ Weber KT, Swamynathan SK, Guntaka RV, Sun Y (1999). "Angiotensin II and extracellular matrix homeostasis". The International Journal of Biochemistry & Cell Biology. 31 (3–4): 395–403. doi:10.1016/s1357-2725(98)00125-3. PMID   10224666.
  9. ↑ Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA (January 2005). "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. Bibcode:2005PNAS..102..437S. doi: 10.1073/pnas.0408704102 . PMC   544320 . PMID   15625103.
  10. ↑ Villarreal FJ, Lee AA, Dillmann WH, Giordano FJ (April 1996). "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. doi:10.1006/jmcc.1996.0068. PMID   8732501.
  11. ↑ Eghbali M, Tomek R, Sukhatme VP, Woods C, Bhambi B (August 1991). "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. doi: 10.1161/01.res.69.2.483 . PMID   1860186.
  12. ↑ Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (May 2002). "Myofibroblasts and mechano-regulation of connective tissue remodelling". Nature Reviews. Molecular Cell Biology. 3 (5): 349–63. doi:10.1038/nrm809. PMID   11988769. S2CID   3353563.
  13. ↑ Boluyt MO, O'Neill L, Meredith AL, Bing OH, Brooks WW, Conrad CH, Crow MT, Lakatta EG (July 1994). "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. doi: 10.1161/01.res.75.1.23 . PMID   8013079.
  14. ↑ Hein S, Arnon E, Kostin S, Schönburg M, Elsässer A, Polyakova V, Bauer EP, Klövekorn WP, Schaper J (February 2003). "Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms". Circulation. 107 (7): 984–91. doi: 10.1161/01.cir.0000051865.66123.b7 . PMID   12600911.
  15. 1 2 Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massagué J (July 1998). "Determinants of specificity in TGF-beta signal transduction". Genes & Development. 12 (14): 2144–52. doi:10.1101/gad.12.14.2144. PMC   317013 . PMID   9679059.
  16. ↑ Wang Y, de Waard MC, Sterner-Kock A, Stepan H, Schultheiss HP, Duncker DJ, Walther T (2007). "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. doi: 10.1016/j.ejheart.2007.02.006 . PMID   17407830.
  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 (March 2006). "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. Bibcode:2006PNAS..103.4735L. doi: 10.1073/pnas.0510019103 . PMC   1450239 . PMID   16537417.
  18. ↑ Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM (2009). "Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications". CGMP: Generators, Effectors and Therapeutic Implications. Handbook of Experimental Pharmacology. Vol. 191. pp. 341–66. doi:10.1007/978-3-540-68964-5_15. ISBN   978-3-540-68960-7. PMC   4855512 . PMID   19089336.
  19. ↑ Kenchaiah S, Pfeffer MA (January 2004). "Cardiac remodeling in systemic hypertension". The Medical Clinics of North America. 88 (1): 115–30. doi:10.1016/s0025-7125(03)00168-8. PMID   14871054. S2CID   32530917.
  20. ↑ Ichiki T, Huntley BK, Sangaralingham SJ, Chen HH, Burnett Jr JC (2009). "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. doi:10.1016/j.cardfail.2009.06.318.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.