Atherosclerosis · 2026
Inflammasome inhibition in myocardial infarction reduces early reperfusion injury and suppresses systemic plaque activation.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Karnewar Santosh, Nguyen The Anh, Ozawa Koya, Huang Weiting, Varli Onur, Morello Matteo, Lindner Emma L, Casarez Eli V, Xie Aris, López José A, Kelly Jazmin, Toldo Stefano, Abbate Antonio, Lindner Jonathan R
Аннотация
BACKGROUND AND AIMS: Activation of innate immunity early after reperfused myocardial infarction (MI) contributes to reperfusion injury and acts systemically to accelerate atherosclerosis in remote non-culprit plaques. We hypothesized that inhibition of the NLRP3 inflammasome complex that is activated by damage-associated molecular patterns after MI would suppress these diverse maladaptive responses.
METHODS: In hyperlipidemic Ldlr-/-Apobec1-/- mice, MI was produced by LAD ischemia-reperufsion followed by randomization to no therapy or the NLRP3 inhibitor MCC950 started immediately upon reperfusion. Comprehensive echocardiography was performed at 1 h, 3 days, and 28 days. Echocardiographic molecular imaging for coronary microvascular platelet GPIbα, P-selectin, and VCAM-1 was performed at 1 h. Myocardial inflammation on day 3 was assessed by histology and flow cytometry, while infarct size and remote brachiocephalic artery plaque were assessed by histology on day 28.
RESULTS: Post-MI treatment with MCC950 suppressed all three molecular imaging markers of microvascular reperfusion injury which was associated with a significant reduction in post-MI myocardial inflammatory cell infiltrate on day 3. Treatment with MCC950 resulted in a greater degree of recovery over time in all echocardiographic measures of LV function, and reduced histologic infarct size by 50% (p < 0.01). Mice undergoing MI had accelerated brachiocephalic plaque growth versus non-ischemic age-matched controls which was inhibited by MCC950 resulting in smaller plaque size and necrotic cores, larger smooth muscle cap thickness, and evidence for fibrous cap endothelial-mesenchymal transformation.
CONCLUSIONS: In reperfused MI, pharmacologic inhibition of the NLRP3 inflammasome suppresses inflammatory and thromboinflammatory processes that contribute to early reperfusion injury, infarct expansion, and remote non-culprit plaque activation in later phases.
METHODS: In hyperlipidemic Ldlr-/-Apobec1-/- mice, MI was produced by LAD ischemia-reperufsion followed by randomization to no therapy or the NLRP3 inhibitor MCC950 started immediately upon reperfusion. Comprehensive echocardiography was performed at 1 h, 3 days, and 28 days. Echocardiographic molecular imaging for coronary microvascular platelet GPIbα, P-selectin, and VCAM-1 was performed at 1 h. Myocardial inflammation on day 3 was assessed by histology and flow cytometry, while infarct size and remote brachiocephalic artery plaque were assessed by histology on day 28.
RESULTS: Post-MI treatment with MCC950 suppressed all three molecular imaging markers of microvascular reperfusion injury which was associated with a significant reduction in post-MI myocardial inflammatory cell infiltrate on day 3. Treatment with MCC950 resulted in a greater degree of recovery over time in all echocardiographic measures of LV function, and reduced histologic infarct size by 50% (p < 0.01). Mice undergoing MI had accelerated brachiocephalic plaque growth versus non-ischemic age-matched controls which was inhibited by MCC950 resulting in smaller plaque size and necrotic cores, larger smooth muscle cap thickness, and evidence for fibrous cap endothelial-mesenchymal transformation.
CONCLUSIONS: In reperfused MI, pharmacologic inhibition of the NLRP3 inflammasome suppresses inflammatory and thromboinflammatory processes that contribute to early reperfusion injury, infarct expansion, and remote non-culprit plaque activation in later phases.
Предметные рубрики MeSH
AnimalsMyocardial InfarctionMyocardial Reperfusion InjuryPlaque, AtheroscleroticInflammasomesNLR Family, Pyrin Domain-Containing 3 ProteinDisease Models, AnimalMice, KnockoutSulfonamidesMaleSulfonesMice, Inbred C57BLHeterocyclic Compounds, 4 or More RingsIndenesMyocardiumMiceTime FactorsAnti-Inflammatory AgentsImmunity, InnateFurans