TAX1BP1 protects against myocardial infarction-associated cardiac anomalies through inhibition of inflammasomes in a RNF34/MAVS/NLRP3-dependent manner

Acute myocardial infarction(MI),one of the most common cardiovascular emergencies,is a leading cause of morbidity and mortality.Ample evidence has revealed an essential role for inflammasome activation and autophagy in the pathogenesis of acute MI.Tax1-binding protein 1(TAX1BP1),an adaptor molecule involved in termination of proinflammatory signaling,serves as an important selective autophagy adaptor,but its role in cardiac ischemia remains elusive.This study examined the role of TAX1BP1 in myocardial ischemic stress and the underlying mechanisms involved.Levels of TAX1BP1 were significantly downregulated in heart tissues of patients with ischemic heart disease and in a left anterior descending(LAD)ligation-induced model of acute MI.Adenovirus carrying TAX1BP1 was delivered into the myocardium.The acute MI induced procedure elicited an infarct and cardiac dysfunction,the effect of which was mitigated by TAX1BP1 overexpression with little effect from viral vector alone.TAX1BP1 nullified acute MI-induced activation of the NLRP3 inflammasome and associated mitochondrial dysfunction.TAX1BP1 overexpression suppressed NLRP3 mitochondrial localization by inhibiting the interaction of NLRP3 with mitochondrial antiviral signaling protein(MAVS).Further investigation revealed that ring finger protein 34(RNF34)was recruited to interact with TAX1BP1 thereby facilitating autophagic degradation of MAVS through K27-linked polyubiquitination of MAVS.Knockdown of RNF34 using siRNA nullified TAX1BP1 yielded protection against hypoxia-induced MAVS mitochondrial accumulation,NLRP3 inflammasome activation and associated loss of mitochondrial membrane potential.Taken together,our results favor a cardioprotective role for TAX1BP1 in acute MI through repression of inflammasome activation in a RNF34/MAVS-dependent manner.

Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction

Mesenchymal stem cells(MSCs)delivered into the post-ischemic heart milieu have a low survival and retention rate,thus restricting the cardioreparative efficacy of MSC-based therapy.Chronic ischemia results in metabolic reprogramming in the heart,but little is known about how these metabolic changes influence implanted MSCs.Here,we found that excessive branched-chain amino acid(BCAA)accumulation,a metabolic signature seen in the post-ischemic heart,was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs.Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation(H3K9me3).A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition.Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy.We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism,emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits.