Introduction:
Elevated level of serum homocysteine (Hcy) has been identified as a risk factor for accelerating progression of cardiovascular disease. Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation by damaged mitochondria results in caspase-1 dependent inflammatory form of cell death.
Methods and Results:
AMI procedure was performed on hCBS/m
cbs
knockout mice at the age of 10weeks. Caspase-1 activity and myocardiocyte apoptosis were observed at the early stage of post-MI in severe HHcy mice (Hcy,120-220μM). Severe HHcy remarkably aggravated infarction size, cardiomyocyte area, and interstitial fibrosis 6 weeks after MI from 22.7 ± 4.3%, 340 ± 54μm
2
, 13.9 ± 1.9% in control mice (Hcy, 7-10μM) to 33.6 ± 6.5%, 485 ± 65μm
2
, 26 ± 4.5%, respectively, (
P
=0.035,
P
= 0.041,
P
=0.002). In the meantime, HHcy significantly increased LV cavity dilatation and dysfunction as compared with control mice by echocardiography (5.9 ± 0.2 vs. 4.2 ± 0.4mm,
P=
0.039; LV ejection fraction, 22.6 ± 3.9% vs. 36.8 ± 4.0%,
P
=0.011). Cultured neonatal mouse ventricular myocyte (NMVM) treated with the combination of DL-Hcy (500μM, 48h) and hypoxia (0.5% O2) showed that increased NLRP3 and caspase1 expression and activity, mitochondrial reactive oxygen species (mtROS) and mtDNA production, dissipation of mitochondrial membrane potential, and mitochondrial permeabilization. Moreover, synergetic effect of Hcy and hypoxia led to pronounced accumulation of damaged mitochondrial through suppressing mitophagy of damaged mitochondria. Caspase-1 activity and myocardiocyte death were lessened as NMVMs were administrated with mitochondria-targeted antioxidant Mito-temple and SOD2, whereas caspase-1 inhibition was not able to fully rescue damaged mitochondria.
Conclusion:
Acute myocardial infarction (AMI) initiates an intense inflammatory response in myocardium that promotes myocardiocyte death, ventricular remodeling, and cardiac dysfunction. Hcy accelerates cardiomyocyte death post-MI in part through mitochondrial-mediated NLRP3 inflammasome activation and inflammation, which contributes to adverse cardiac remodeling, ventricular dysfunction, and heart failure.
NLRP3 Inflammasome Is Involved in Calcium-Sensing Receptor-Induced Aortic Remodeling in SHRs