Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets.
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.
['Xu|Yanyan|Y|', 'Jiang|Haojie|H|', 'Li|Li|L|', 'Chen|Fengwu|F|', 'Liu|Yunxia|Y|', 'Zhou|Meiyi|M|', 'Wang|Ji|J|', 'Jiang|Jingjing|J|', 'Li|Xiaoying|X|', 'Fan|Xuemei|X|', 'Zhang|Lin|L|', 'Zhang|Junfeng|J|', 'Qiu|Junqiang|J|', 'Wu|Yi|Y|', 'Fang|Chao|C|', 'Sun|Haipeng|H|', 'Liu|Junling|J|']
D000597:Amino Acids, Branched-Chain D000818:Animals D015415:Biomarkers D001780:Blood Coagulation Tests D001792:Blood Platelets D003924:Diabetes Mellitus, Type 2 D004195:Disease Models, Animal D004198:Disease Susceptibility D004734:Energy Metabolism D006801:Humans D050356:Lipid Metabolism D024821:Metabolic Syndrome D051379:Mice D018345:Mice, Knockout D010084:Oxidation-Reduction D015539:Platelet Activation D013927:Thrombosis D051348:Tropomodulin
thrombosis TMOD protein, human amino acids, branched-chain blood platelets metabolic syndrome