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

Molecules. 2021 Jun 9;26(12):3534. doi: 10.3390/molecules26123534.

Abstract

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.

Keywords: NLRP3; acute myocardial infarction; heart failure; inflammasome; inflammation.

MeSH terms

  • Animals
  • Anterior Wall Myocardial Infarction / drug therapy*
  • Anterior Wall Myocardial Infarction / metabolism
  • Anterior Wall Myocardial Infarction / pathology
  • Anti-Inflammatory Agents / pharmacology
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Diastole
  • Disease Models, Animal
  • Inflammasomes / antagonists & inhibitors
  • Male
  • Mice
  • Mice, Inbred ICR
  • Myocardial Contraction
  • Myocardial Ischemia / drug therapy*
  • Myocardial Ischemia / metabolism
  • Myocardial Ischemia / pathology
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • Nitriles / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nitriles
  • Nlrp3 protein, mouse
  • dapansutrile

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