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Prevention and rescue of cardiac dysfunction by methanocarba adenosine monophosphonate derivatives

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Abstract

Accumulating evidence supports a therapeutic role of purinergic signaling in cardiac diseases. Previously, efficacy of systemically infused MRS2339, a charged methanocarba derivative of 2-Cl-adenosine monophosphate, was demonstrated in animal models of heart failure. We now test the hypothesis that an uncharged adenine nucleoside phosphonate, suitable as an oral agent with a hydrolysis-resistant phospho moiety, can prevent the development of cardiac dysfunction in a post-infarction ischemic or pressure overload-induced heart failure model in mice. The diester-masked uncharged phosphonate MRS2978 was efficacious in preventing cardiac dysfunction with improved left ventricular (LV) fractional shortening when administered orally at the onset of ischemic or pressure overload-induced heart failure. MRS2925, the charged, unmasked MRS2978 analog, prevented heart dysfunction when infused subcutaneously but not by oral gavage. When administered orally or systemically, MRS2978 but not MRS2925 could also rescue established cardiac dysfunction in both ischemic and pressure overload heart failure models. The diester-masked phosphate MRS4074 was highly efficacious at preventing the development of dysfunction as well as in rescuing pressure overload-induced and ischemic heart failure. MRS2978 was orally bioavailable (57–75%) giving rise to MRS2925 as a minor metabolite in vivo, tested in rats. The data are consistent with a novel therapeutic role of adenine nucleoside phosphonates in systolic heart failure.

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Abbreviations

CSQ:

Calsequestrin

EF:

Ejection fraction

FS:

Fractional shortening

SV:

Stroke volume

HRMS:

High resolution mass spectrometry

LAD:

Left anterior descending artery

LVPW:

Left ventricular posterior wall

LVEDD:

Left ventricular end-diastolic diameter

LVESD:

Left ventricular end-systolic diameter

MRS2339:

(1′S,2′R,3′S,4′R,5′S)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl] bicyclo[3.1.0]hexane-2,3-diol)

MRS2978:

diisopropyl (2-((1′S,2′R,3′S,4′R,5′S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)ethyl)phosphonate

MRS4074:

((1′R,2′R,3′S,4′R,5′S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)methyl diisopropyl phosphate

MRS2925:

(2-((1′S,2′R,3′S,4′R,5′S)-4-(6-amino-2-chloro-9H-purin-9-yl)-2,3-dihydroxybicyclo[3.1.0]hexan-1-yl)ethyl)phosphonic acid

P2XR:

P2X receptor

TAC:

Transverse aorta constriction

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Funding

KAJ received support from the NIDDK Intramural Research Program (ZIADK31127). This work was supported by the Calhoun Cardiology Research Endowment and HL48225 to BTL.

Author information

Correspondence to Bruce T. Liang.

Ethics declarations

Conflicts of interest

Jian-Bing Shen declares that he has no conflict of interest.

Kiran S. Toti declares that he has no conflict of interest.

Saibal Chakraborty declares that he has no conflict of interest.

T. Santhosh Kumar declares that he has no conflict of interest.

Chunxia Cronin declares that she has no conflict of interest.

Bruce T. Liang declares that he has no conflict of interest.

Kenneth A. Jacobson declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants. The animal protocols were reviewed and approved by the Institutional Animal Ethics Committees at each institution where animal experiments were performed.

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Jian-Bing Shen and Kiran S. Toti are co-equal authors.

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Shen, J., Toti, K.S., Chakraborty, S. et al. Prevention and rescue of cardiac dysfunction by methanocarba adenosine monophosphonate derivatives. Purinergic Signalling (2020). https://doi.org/10.1007/s11302-020-09688-0

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Keywords

  • Purinergic receptors
  • Adenine nucleoside phosphonate
  • Cardiac function
  • Heart failures