Design and characterization of the first peptidomimetic molecule that prevents acidification-induced closure of cardiac gap junctions

Verma, Vandana; Larsen, Bjarne Due; Coombs, Wanda; Lin, Xianming; Sarrou, Eliana; Taffet, Steven M.; Delmar, Mario

doi:10.1016/j.hrthm.2010.06.028

Cited by 21 publications

(13 citation statements)

References 20 publications

(47 reference statements)

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“…Our findings that enhanced phosphorylation of Cxs and reduced abundance of Cx37 in renin-secreting cells are associated with little involvement of Cx37 and Cx40 in renal autoregulation in diabetes seem to agree with our previous studies, in which conductance of vascular gap junctions was subject to pathophysiological modulations [23]. A recent report that peptidomimetic molecules prevent closure of cardiac Cx43 gap junctions points to a possible basis for the development of new therapeutic tools for diabetic nephropathy [24].…”

Section: Introductionsupporting

confidence: 92%

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

et al. 2011

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Aims/hypothesis We examined the link between altered gap junctional communication and renal haemodynamic abnormalities in diabetes in studies performed on Zucker lean (ZL) and the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. Methods The abundance of connexin (Cx) 37, 40 and 43 was assessed by western blot and immunohistochemistry. Renal haemodynamics was characterised with GAP peptides, which are Cx mimetics, to inhibit gap junctions as a probe in both strains. Results ZDF rats exhibited higher plasma glucose, 8-epiprostaglandin F2α excretion, renal plasma flow and GFR than ZL rats. In ZDF rat kidney phosphorylation of Cx43 was enhanced compared with that in ZL rats. Immunohistochemical study revealed that the density of abundance of Cx37 in renin-secreting cells was significantly reduced in ZDF rats. Although renal autoregulation was markedly impaired in ZDF rats, it was preserved in ZL rats. GAP27 for Cx37,43 and for Cx40 impaired renal autoregulation in ZL rats, but failed to induce further alterations in renal autoregulation in ZDF rats. Conclusions/interpretation Our findings indicate that ZDF rats have glomerular hyperfiltration with impaired autoregulation. They also demonstrate enhanced phosphorylation of Cxs and reduced production of Cxs in ZDF rat kidney, especially of Cx37 in renin-secreting cells. Finally, our data suggest that an impairment of gap junctional communication in juxtaglomerular apparatus plays a role in altered renal autoregulation in diabetes.

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Section: Introductionsupporting

confidence: 92%

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

et al. 2011

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“…In silico analysis, validated experimentally, further showed that the triangular secondary structure formed by the two arginines and the tyrosine side chains (a “pharmacophore triangle”) serves as platform for the design of synthetic molecules that target cardiac gap junction channels. These experiments led to the first peptidomimetic compound capable of preventing chemical gating of Cx43 (compound “ZP2519”) (723) and demonstrated that rational, structure-based drug design can be applied to cardiac gap junction pharmacology. These molecules can then serve as tools to determine the role of gap junction regulation in cardiac arrhythmogenesis and, potentially, serve as pharmacological agents for treatment of a selected subset of cardiac arrhythmias.…”

Section: Pharmacology Of Gap Junctionsmentioning

confidence: 99%

Gap Junctions

Nielsen,

Nygaard Axelsen,

Sorgen

et al. 2012

Comprehensive Physiology

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365

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Gap junctions are essential to the function of multicellular animals, which require a high degree of coordination between cells. In vertebrates, gap junctions comprise connexins and currently 21 connexins are known in humans. The functions of gap junctions are highly diverse and include exchange of metabolites and electrical signals between cells, as well as functions, which are apparently unrelated to intercellular communication. Given the diversity of gap junction physiology, regulation of gap junction activity is complex. The structure of the various connexins is known to some extent; and structural rearrangements and intramolecular interactions are important for regulation of channel function. Intercellular coupling is further regulated by the number and activity of channels present in gap junctional plaques. The number of connexins in cell‐cell channels is regulated by controlling transcription, translation, trafficking, and degradation; and all of these processes are under strict control. Once in the membrane, channel activity is determined by the conductive properties of the connexin involved, which can be regulated by voltage and chemical gating, as well as a large number of posttranslational modifications. The aim of the present article is to review our current knowledge on the structure, regulation, function, and pharmacology of gap junctions. This will be supported by examples of how different connexins and their regulation act in concert to achieve appropriate physiological control, and how disturbances of connexin function can lead to disease. © 2012 American Physiological Society. Compr Physiol 2:1981‐2035, 2012.

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“…Arg-Arg-Lys-(4hydroxyl-benzoyl) Binds to the carboxyterminal domain of Cx43 and stabilizes the open state (Verma et al, 2010) Gap 26 Val-Cys-Tyr-Glu-Lys-Ser-Phe-Pro-Iso-Ser-His-Val-Arg Decreases infarct size and area at risk and closes Cx43 hemichannels (Hawat et al, 2010) Gap 27 Ser-Arg-Pro-Thr-Glu-Lys-Thr-Ile-Phe-Ile-Ile…”

Section: Zp2519mentioning

confidence: 99%

“…These cyclic structures were more stable in the cytoplasm, and formed in this way an excellent platform for the next generation of compounds with maximal activity and minimal size to preserve gap junctional communication during arrhythmias (Verma et al, 2009). Recently, Verma et al (2010) described the first RXP-derived peptidomimetic molecule with preserved activity as a gap junction opener: ZP2519 (Table 1) with a molecular weight of 619 Da (Verma et al, 2010). This molecule prevented acidification-induced uncoupling in cardiac gap junctions and in N2A cells stably transfected with Cx43 (Verma et al, 2010).…”

Section: Future Prospectives: Rxp-peptides As Antiarrhythmic Agentsmentioning

confidence: 99%

“…Recently, Verma et al (2010) described the first RXP-derived peptidomimetic molecule with preserved activity as a gap junction opener: ZP2519 (Table 1) with a molecular weight of 619 Da (Verma et al, 2010). This molecule prevented acidification-induced uncoupling in cardiac gap junctions and in N2A cells stably transfected with Cx43 (Verma et al, 2010). ZP2519 had no influence on the gap junctional communication of Cx40 expressing cells.…”

Section: Future Prospectives: Rxp-peptides As Antiarrhythmic Agentsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

Vuyst¹,

Boengler²,

Antoons³

et al. 2011

British J Pharmacology

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Coordinated electrical activity in the heart is supported by gap junction channels located at the intercalated discs of cardiomyocytes. Impaired gap junctional communication between neighbouring cardiomyocytes contributes to the development of re-entry arrhythmias after myocardial ischaemia. Current antiarrhythmic therapy is hampered by a lack of efficiency and side effects, creating the need for a new generation of drugs. In this review, we focus on compounds that increase gap junctional communication, thereby increasing the conduction velocity and decreasing the risk of arrhythmias. Some of these compounds also inhibit connexin 43 (Cx43) hemichannels, thereby limiting adenosine triphosphate loss and volume overload following ischaemia/reperfusion, thus potentially increasing the survival of cardiomyocytes. The compounds discussed in this review are: (i) antiarrythmic peptide (AAP), AAP10, ZP123; (ii) GAP-134; (iii) RXP-E; and (vi) the Cx mimetic peptides Gap 26 and Gap 27. None of these compounds have effects on Na + , Ca 2+ and K + channels, and therefore have no proarrhythmic activity associated with currently available antiarrhythmic drugs. GAP-134, RXP-E, Gap 26 and Gap 27 are pharmalogical agents with a favorable clinical safety profile, as already confirmed in phase I clinical trials for GAP-134. These agents show an excellent promise for treatment of arrhythmias in patients with ischaemic cardiomyopathy.

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Design and characterization of the first peptidomimetic molecule that prevents acidification-induced closure of cardiac gap junctions

Abstract: Background-Gap junctions are potential targets for pharmacological intervention. We have previously developed a series of peptide sequences that prevent closure of Cx43 channels, bind to cardiac Cx43 and prevent acidification-induced uncoupling of cardiac gap junctions.

Cited by 21 publications

References 20 publications

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

Gap Junctions

Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

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