Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo.
Animals
Cardiotonic Agents
/ chemical synthesis
Cell Line
Disease Models, Animal
Esters
/ chemistry
Female
Humans
Male
Malonates
/ chemical synthesis
Mice
Mice, Inbred C57BL
Mitochondria
/ drug effects
Myocardial Infarction
/ prevention & control
Myocardial Reperfusion Injury
/ drug therapy
Prodrugs
Rats
Rats, Wistar
Reactive Oxygen Species
/ metabolism
Succinic Acid
/ metabolism
Drug delivery
Ischemia/reperfusion injury
Malonate
Mitochondria
Succinate
Journal
Cardiovascular drugs and therapy
ISSN: 1573-7241
Titre abrégé: Cardiovasc Drugs Ther
Pays: United States
ID NLM: 8712220
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
accepted:
26
06
2020
pubmed:
11
7
2020
medline:
23
2
2022
entrez:
11
7
2020
Statut:
ppublish
Résumé
Mitochondrial reactive oxygen species (ROS) production upon reperfusion of ischemic tissue initiates the ischemia/reperfusion (I/R) injury associated with heart attack. During ischemia, succinate accumulates and its oxidation upon reperfusion by succinate dehydrogenase (SDH) drives ROS production. Inhibition of succinate accumulation and/or oxidation by dimethyl malonate (DMM), a cell permeable prodrug of the SDH inhibitor malonate, can decrease I/R injury. However, DMM is hydrolysed slowly, requiring administration to the heart prior to ischemia, precluding its administration to patients at the point of reperfusion, for example at the same time as unblocking a coronary artery following a heart attack. To accelerate malonate delivery, here we developed more rapidly hydrolysable malonate esters. We synthesised a series of malonate esters and assessed their uptake and hydrolysis by isolated mitochondria, C2C12 cells and in mice in vivo. In addition, we assessed protection against cardiac I/R injury by the esters using an in vivo mouse model of acute myocardial infarction. We found that the diacetoxymethyl malonate diester (MAM) most rapidly delivered large amounts of malonate to cells in vivo. Furthermore, MAM could inhibit mitochondrial ROS production from succinate oxidation and was protective against I/R injury in vivo when added at reperfusion. The rapidly hydrolysed malonate prodrug MAM can protect against cardiac I/R injury in a clinically relevant mouse model.
Identifiants
pubmed: 32648168
doi: 10.1007/s10557-020-07033-6
pii: 10.1007/s10557-020-07033-6
pmc: PMC8770414
mid: EMS128238
doi:
Substances chimiques
Cardiotonic Agents
0
Esters
0
Malonates
0
Prodrugs
0
Reactive Oxygen Species
0
malonic acid
9KX7ZMG0MK
Succinic Acid
AB6MNQ6J6L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1-13Subventions
Organisme : National Natural Science Foundation of China
ID : 81411130138
Organisme : Medical Research Council
ID : MC_U105663142
Pays : United Kingdom
Organisme : Medical Research Council UK
ID : MR/P000320/1
Organisme : Wellcome Trust
ID : 110158/Z/15/Z
Pays : United Kingdom
Organisme : Key Programme
ID : 16JCZDJC35000
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110159
Pays : United Kingdom
Organisme : Medical Research Council UK
ID : MC_U105663142
Organisme : British Heart Foundation
ID : PG/15/84/31670
Pays : United Kingdom
Organisme : National Natural Science Foundation of China
ID : 81470397
Organisme : Wellcome Trust
ID : 110158
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110159/Z/15/Z
Pays : United Kingdom
Organisme : National Natural Science Foundation of China
ID : 81270182
Informations de copyright
© 2020. The Author(s).
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