PKM2 Activator TEPP-46 Attenuates Thoracic Aortic Aneurysm and Dissection by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion

Abstract

Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far. Approach and Results: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)–induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain–containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α. Conclusion: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.

Activator-Mediated Pyruvate Kinase M2 Activation Contributes to Endotoxin Tolerance by Promoting Mitochondrial Biogenesis

“…found that PKM2 activator TEPP-46 attenuates β-aminopropionitrile fumarate (BAPN)-induced mouse model of thoracic aortic aneurysm and dissection (TAAD) by inhibiting NLRP3 inflammasome-mediated IL-1β secretion. This provides a new treatment strategy for TAAD ( 55 ). In this study, we have shown direct evidence of PKM2 tetramer-mediated macrophage endotoxin tolerance in primary macrophages (PMs and KCs), as well as in the RAW264.7 cell line.…”

Deciphering the Role of Interleukin-1β in the Development of Dissecting Thoracic Aortic Aneurysm

“…2 So far, only a few studies have investigated its role using a BAPN induced dissecting model of TAA. 1,3,4 Interestingly, the administration of BAPN was associated with a local, but not systemic, increased expression of IL-1b in the aorta. 3 In another study, the use of enzyme pyruvate kinase M2 activator TEPP-46 demonstrated its efficacy to attenuate TAA formation by inhibiting pyrin domain containing protein 3 inflammasome, which was associated with a decrease in IL-1b expression in the thoracic aorta.…”

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

“…These findings were further supported by Li et al demonstrating that co-treatment of human monocytic THP-1 cells with TEPP-46 and 2-deoxy-D-glucose reversed hyperglycemia-induced NLRP3 activation [ 185 ] ( Figure 2 ). Conversely, TEPP-46-mediated activation of PKM2 inhibited NLRP3 inflammasome-mediated IL-1β secretion in a β-aminopropionitrile fumarate (BAPN)-treated mouse model of thoracic aortic aneurysm and dissection (TAAD) [ 186 ]. These findings are in line with those of the O’Neill group, demonstrating that PKM2 activation in vivo using TEPP inhibits IL-1β production in an experimental model of Salmonella typhimurium infection [ 128 ].…”