Hydroxychloroquine can reduce myocardial ischaemia and post-ischemic reperfusion injury

Immune-mediated myocardial injury has been associated
with a variety of heart conditions, including ischaemic heart disease.
There is growing clinical evidence that acute myocardial infarction, IRI, and left ventricular remodeling after myocardial infarction are associated
with an enhanced immune response.
When injury-associated molecular patterns (DAMPs) released by damaged cardiomyocytes interact with pattern-recognition receptors (PRRs), innate immune-mediated inflammatory responses
are activated.
In PRR, Toll-like receptors (TLRs) are particularly considered to be key elements
in mediating the inflammatory response of acute myocardial infarction and myocardial IRI.
Once released into the blood during ischemia-reperfusion, DAMPs such as cell-free DNA (cfDNA) and high-mobility group box-1 (HMGB1) activate receptors of the advanced glycosylation end product (RAGE)-TLR9 pathway to trigger an inflammatory response
.
cfDNA also activates plasma cell-like dendritic cells (pDCs) to release type I interferons (IFN-Is), including interferon α and β (IFNα and IFNβ).

IFN-Is, in turn, mediates ischemic reperfusion injury
.

HCQ exhibits potent anti-inflammatory properties
by inhibiting TLR9 and IFN-is in pDCs.
HCQ also showed a protective effect against kidney, skeletal muscle and myocardial IRI when administered before an ischemic attack, but the role of HCQ after the onset of myocardial infarction remains unknown
.
The investigators hypothesized that the TLR9-IFN-I pathway is activated during acute myocardial infarction and mediates ischemic myocardial injury and ischemic reperfusion injury
.
Since HCQ inhibits the TLR9-IFN-I pathway, it is further hypothesized that administration of HCQ will attenuate the inflammatory response and associated ischemia-reperfusion injury
.
If administered before an ischemic attack, ischemic injury
from myocardial infarction should be additionally mitigated.

Methods: Left coronary artery occlusion in wild-type (WT) C57BL/6 and homologous TLR9 mice for 40 min with or without 60 min of reperfusion (40'/0' or 40'/60').

ODN-2088 or HCQ (TLR9 inhibitor) or ODN-1826 (TLR9 agonist) is given to determine the effect
on infarct size (IS).
After 40'/0', collect cardiac perfusion fluid (CP) from harvested hearts and give intact WT mice or isolated splenocytes 20 min after ischemia
.
Interferon type I (IFNα and IFNβ) levels are measured in plasma and splenocytes culture supernatants, and levels of damage-related molecular patterns HMGB1 and cell-free DNA (cfDNA) are measured in CP
.

Results: After 40'/60', IS was significantly reduced
in WT mice treated with HCQ or ODN-2088.
TLR9 mice and HCQ-treated WT mice experienced similar attenuated IS at 40'/0' and 40'/60', with significantly lower
IFN-is in CP after 40'/0' and IFN-Is in plasma after 40'/60'.
IS was significantly increased
in 20'/60' WT mice treated with 40'/0' CP and ODN-1826.
CP-treated WT splenocytes produced significantly higher IFN-I in culture supernatants, and HCQ significantly reduced IFN-I
.

Conclusion: TLR9-IFN-I-mediated inflammatory response has significant contributions
to ischemic and post-ischemic myocardial ischemia-reperfusion injury.
HMGB1 and cfDNA released from ischemic myocardium activate intramyocardial TLR9-IFN-I inflammatory pathways during ischemia and extramyocardial TLR9-IFN-I inflammatory pathways
during reperfusion.
Hydroxychloroquine reduces IFN-I production and weakens myocardial IRI, possibly by inhibiting the TLR9-IFN-I pathway
.

References:

Marsh KM, Rastogi R, Zhang A, Wu D, Kron IL, Yang Z.
Hydroxychloroquine Attenuates Myocardial Ischemic and Post-Ischemic Reperfusion Injury by Inhibiting the Toll-Like Receptor 9 - Type I Interferon Pathway.
Cardiol Cardiovasc Med.
2022; 6(4):416-423.
doi: 10.
26502/fccm.
92920278.
Epub 2022 Aug 25.
PMID: 36081846; PMCID: PMC9450995.