Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177(®) (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction.
Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177(®) (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction.
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DOI：
10.3390/molecules26123534
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发表时间：
2021-06-09
期刊：
影响因子：
--
通讯作者：
Toldo S
中科院分区：
文献类型：
--
作者：
Aliaga J;Bonaventura A;Mezzaroma E;Dhakal Y;Mauro AG;Abbate A;Toldo S
白细胞介素-1 β（IL-1β）是NLRP 3炎性体的产物，调节心脏收缩力和舒张功能。我们提出，新型NLRP 3抑制剂OLT 1177 ®（达潘舒曲）可以保护心肌梗死（MI）后的收缩储备和舒张功能。我们通过结扎左冠状动脉而不进行再灌注，使用严重缺血性心肌病的实验性小鼠模型，7天后随机分配显示大前壁MI的小鼠（>4个运动不能节段），左心室（LV）尺寸增加（[LVEDD] > 4.4 mm），简化函数（LV射血分数< 40%）添加到富含与食物混合的3.75 g/kg的OLT 1177 ®饮食中（组1 [n = 10]）或7.5 g/kg（组2 [n = 9]），或作为未处理对照组的标准饮食（组3 [n = 10]）持续9周。在MI手术后10周，我们用异丙肾上腺素激发法测定心功能和收缩储备，用心导管法测定舒张功能。当与对照（组3）相比时，用OLT 1177处理的小鼠（组1和组2）显示出显著更大的收缩储备保留（异丙肾上腺素激发后左心室射血分数[LVEF]的百分比增加为+33 ± 11%和+40 ± 6%，而标准饮食为+9 ± 7%;第1组和第2组分别为p < 0.05和p < 0.005）和舒张功能（测量为左心室舒张末期压降低（3.2 ± 0.5 mmHg或4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg;分别为p < 0.005和p < 0.009）。MI组的静息LVEF之间无差异。这些作用与对心肌梗死后心室重构的影响无关。在大型非再灌注前壁心肌梗死小鼠模型中，使用OLT 1177 ®抑制NLRP 3炎性小体可保持β-肾上腺素能反应性并预防左心室舒张功能障碍。因此，OLT 1177 ®可用于预防缺血性心肌病患者发生心力衰竭。
Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve β-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.
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DOI：
10.1073/pnas.2000915118
发表时间：
2021-03-09
影响因子：
11.1
作者：
Tengesdal IW;Menon DR;Osborne DG;Neff CP;Powers NE;Gamboni F;Mauro AG;D'Alessandro A;Stefanoni D;Henen MA;Mills TS;De Graaf DM;Azam T;Vogeli B;Palmer BE;Pietras EM;DeGregori J;Tan AC;Joosten LAB;Fujita M;Dinarello CA;Marchetti C
通讯作者：
Marchetti C
DOI：
10.1073/pnas.0611496104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Duncan, Joseph A.;Bergstralht, Daniel T.;Ting, Jenny Pan-Yun
通讯作者：
Ting, Jenny Pan-Yun
DOI：
10.1073/pnas.1716095115
发表时间：
2018-02-13
影响因子：
11.1
作者：
Marchetti C;Swartzwelter B;Gamboni F;Neff CP;Richter K;Azam T;Carta S;Tengesdal I;Nemkov T;D'Alessandro A;Henry C;Jones GS;Goodrich SA;St Laurent JP;Jones TM;Scribner CL;Barrow RB;Altman RD;Skouras DB;Gattorno M;Grau V;Janciauskiene S;Rubartelli A;Joosten LAB;Dinarello CA
通讯作者：
Dinarello CA
白介素-1和炎性体作为心血管疾病的治疗靶标。
影响因子：
20.1
作者：
Abbate A;Toldo S;Marchetti C;Kron J;Van Tassell BW;Dinarello CA
通讯作者：
Dinarello CA
影响因子：
20.1
作者：
Gao E;Lei YH;Shang X;Huang ZM;Zuo L;Boucher M;Fan Q;Chuprun JK;Ma XL;Koch WJ
通讯作者：
Koch WJ