Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets

Abstract

Background: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. Methods: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm–deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. Results: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P <0.001) and arterial thrombosis formation in mice (n=9; P <0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P <0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbβ3–mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbβ3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbβ3–mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P <0.05). Conclusions: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome–associated thrombophilia.

Serum Metabolic Profiles Based on Nuclear Magnetic Resonance Spectroscopy among Patients with Deep Vein Thrombosis and Healthy Controls

“…The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important resources for energy production and regulators of metabolic and nutrient signals. BCAA catabolism is a regulator of platelet activation, and BCAA dysfunction could be associated with arterial thrombosis risk [42]. Although BCAAs have not yet been reported to be associated with venous thrombosis, in this study, we showed alterations in leucine, valine, alanine, and lipoproteins in the thrombosis group (Figure A1).…”

Roxadustat Does Not Affect Platelet Production, Activation, and Thrombosis Formation

“…The aggregation of washed platelets was performed as described previously 15 on a whole-blood lumiaggregometer (Chrono-Log, Havertown, PA) upon stimulation with the indicated agonists including thrombin, ADP, U46619, and collagen. Platelet spreading was performed as before.…”

The LEPIS-HuR-TMOD4 axis regulates hepatic cholesterol homeostasis and accelerates atherosclerosis

“…Tropomodulin was originally discovered to be a protein that binds with tropomyosin to regulate the polymerization and depolymerization of actin (Weber, Pennise et al, 1994). Studies have suggested that the propionylation of TMOD3 is associated with platelet activation and arterial thrombosis (Xu, Jiang et al, 2020). The study pointed out that knocking out TMOD1 in systemic tissues other than the heart caused TG and HDL-C metabolism to be abnormal in mice, and this may be a cause of AS (Ding & Xu, 2015).…”