Beta adrenergic receptor kinase carboxyl-terminus

Beta adrenergic receptor kinase carboxyl-terminus (also βARKct) is a peptide composed of the last 194 amino acid residues of the carboxyl-terminus of beta adrenergic receptor kinase 1 (βARK1). It binds the βγ subunits of G proteins located in the plasma membrane of cells.^[1]^[2] It is currently an experimental gene therapy for the treatment of heart failure.

Heart Failure

During heart failure, the heart is not able to pump enough blood to the rest of the body and will begin to undergo processes in order to compensate for its decreased function. These processes will attempt to increase the heart’s output; however, the heart may become overstressed and eventually dysfunctional as a result. The sympathetic nervous system increases norepinephrine release to stimulate β-adrenergic receptors (βARs) located on heart cell (cardiomyocyte) membranes to increase the heart’s rate and force of contraction. If the heart is already stressed or damaged, this will cause the heart to work above its capacity.^[1] Continuous stimulation of the βARs leads to the activation of βARK1 which phosphorylates βARs to decrease their response to norepinephrine and other catecholamines.^[3] βARs are downregulated as a result, decreasing the control over the heart’s rate and force of contraction. A cycle begins as more norepinephrine is produced in an attempt to stimulate the heart to contract.^[4]

Functions

The βARKct peptide acts by binding to Gβγ proteins, competing with βARK1 for the same binding site. βARK1 requires binding to Gβγ protein-coupled receptors to be activated. By inhibiting βARK1, βARs will be upregulated back to a normal range.^[3] With βAR function restored in a failing heart, the force of contraction increases and the levels of catecholamines and growth factors return to normal.^[3]^[4] Additionally, when βARs are activated, βARKct will bind Gβγ proteins to prevent their interaction with and inhibition of the L-type calcium channels (LCC) present on cardiomyocyte plasma membranes.^[5] This increases the flow of calcium ions through the LCCs during depolarization of the cardiomyocyte, increasing calcium levels for contraction to occur. This mechanism has been demonstrated under in vitro conditions and may work with the inhibition of βARK1 to restore βAR function.^[5]

Gene Therapy

The main approach to treatment using βARKct is to insert the gene coding for it into a virus and then infecting cardiomyocytes with it. The virus, containing the βARKct gene, may be injected directly into the left coronary artery or the left ventricular walls following surgical opening of the thorax.^[1]^[4] A less invasive method for transfer is by using a catheter to inject the virus directly into the left coronary artery without opening the chest cavity.^[2]^[3]

Experimental Animal Models

The use of βARKct gene therapy in humans is still under investigation with no trials currently being carried out. The effectiveness of this therapy has been shown in small animal models including mice,^[6] rats,^[4]^[5] and rabbits.^[1]^[2] Larger animal models, such as pig hearts, more resemble the human heart and have also demonstrated the benefits of this therapy and its potential use in humans.^[3]

References

^ ^a ^b ^c ^d White DC, Hata JA, Shah AS, Glower DD, Lefkowitz RJ, Koch WJ (May 2000). "Preservation of myocardial β-adrenergic receptor signaling delays the development of heart failure after myocardial infarction". Proceedings of the National Academy of Sciences. 97 (10): 5428–5433. Bibcode:2000PNAS...97.5428W. doi:10.1073/pnas.090091197. PMC 25845. PMID 10779554.
^ ^a ^b ^c Shah AS, White DC, Emani S, Kypson AP, Lilly RE, Wilson K, Glower DD, Lefkowitz RJ, Koch WJ (March 2001). "In Vivo Ventricular Gene Delivery of a β-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction". Circulation. 103 (9): 1311–1316. doi:10.1161/01.CIR.103.9.1311. PMID 11238278.
^ ^a ^b ^c ^d ^e Raake PW, Schlegel P, Ksienzyk J, Reinkober J, Barthelmes J, Schinkel S, Pleger S, Mier W, Haberkorn U, Koch WJ, Katus HA, Most P, Muller OJ (January 2012). "AAV6.βARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model". European Heart Journal. 34 (19): 1437–1447. doi:10.1093/eurheartj/ehr447. PMC 3653122. PMID 22261894.
^ ^a ^b ^c ^d Rengo G, Lymperopoulos A, Zincarelli C, Donniacuo M, Soltys S, Rabinowitz JE, Koch WJ (January 2009). "Myocardial Adeno-Associated Virus Serotype 6-βARKct Gene Therapy Improves Cardiac Function and Normalizes the Neurohormonal Axis in Chronic Heart Failure". Circulation. 119 (1): 89–98. doi:10.1161/CIRCULATIONAHA.108.803999. PMC 2647661. PMID 19103992.
^ ^a ^b ^c Volkers M, Wedienhammer C, Herzog N, Qiu G, Spaich K, von Wegner F, Peppel K, Muller OJ, Schinkel S, Rabinowitz JE, Hippe H, Brinks H, Katus HA, Koch WJ, Eckhart AD, Friedrich O, Most P (January 2011). "The Inotropic Peptide βARKct improves βAR Responsiveness in Normal and Failing Cardiomyocytes Through Gβγ-Mediated L-Type Calcium Current Disinhibition". Circulation Research. 108 (1): 27–39. doi:10.1161/CIRCRESAHA.110.225201. PMC 4013502. PMID 21106943.
^ Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, Iaccarino G, Koch WJ, Leinwand LA (April 2001). "Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy". The Journal of Clinical Investigation. 107 (8): 967–974. doi:10.1172/JCI12083. PMC 199560. PMID 11306600.

[White-1] White DC, Hata JA, Shah AS, Glower DD, Lefkowitz RJ, Koch WJ (May 2000). "Preservation of myocardial β-adrenergic receptor signaling delays the development of heart failure after myocardial infarction". Proceedings of the National Academy of Sciences. 97 (10): 5428–5433. Bibcode:2000PNAS...97.5428W. doi:10.1073/pnas.090091197. PMC 25845. PMID 10779554.

[Shah-2] Shah AS, White DC, Emani S, Kypson AP, Lilly RE, Wilson K, Glower DD, Lefkowitz RJ, Koch WJ (March 2001). "In Vivo Ventricular Gene Delivery of a β-Adrenergic Receptor Kinase Inhibitor to the Failing Heart Reverses Cardiac Dysfunction". Circulation. 103 (9): 1311–1316. doi:10.1161/01.CIR.103.9.1311. PMID 11238278.

[Raake-3] Raake PW, Schlegel P, Ksienzyk J, Reinkober J, Barthelmes J, Schinkel S, Pleger S, Mier W, Haberkorn U, Koch WJ, Katus HA, Most P, Muller OJ (January 2012). "AAV6.βARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model". European Heart Journal. 34 (19): 1437–1447. doi:10.1093/eurheartj/ehr447. PMC 3653122. PMID 22261894.

[Rengo-4] Rengo G, Lymperopoulos A, Zincarelli C, Donniacuo M, Soltys S, Rabinowitz JE, Koch WJ (January 2009). "Myocardial Adeno-Associated Virus Serotype 6-βARKct Gene Therapy Improves Cardiac Function and Normalizes the Neurohormonal Axis in Chronic Heart Failure". Circulation. 119 (1): 89–98. doi:10.1161/CIRCULATIONAHA.108.803999. PMC 2647661. PMID 19103992.

[Volkers-5] Volkers M, Wedienhammer C, Herzog N, Qiu G, Spaich K, von Wegner F, Peppel K, Muller OJ, Schinkel S, Rabinowitz JE, Hippe H, Brinks H, Katus HA, Koch WJ, Eckhart AD, Friedrich O, Most P (January 2011). "The Inotropic Peptide βARKct improves βAR Responsiveness in Normal and Failing Cardiomyocytes Through Gβγ-Mediated L-Type Calcium Current Disinhibition". Circulation Research. 108 (1): 27–39. doi:10.1161/CIRCRESAHA.110.225201. PMC 4013502. PMID 21106943.

[Freeman-6] Freeman K, Lerman I, Kranias EG, Bohlmeyer T, Bristow MR, Lefkowitz RJ, Iaccarino G, Koch WJ, Leinwand LA (April 2001). "Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy". The Journal of Clinical Investigation. 107 (8): 967–974. doi:10.1172/JCI12083. PMC 199560. PMID 11306600.

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