Branched-chain amino acids in cardiovascular disease

Abstract

Research conducted in the past 15 years has yielded crucial insights that are reshaping our understanding of the systems physiology of branched-chain amino acid (BCAA) metabolism and the molecular mechanisms underlying the close relationship between BCAA homeostasis and cardiovascular health. The rapidly evolving literature paints a complex picture, in which numerous tissue-specific and disease-specific modes of BCAA regulation initiate a diverse set of molecular mechanisms that connect changes in BCAA homeostasis to the pathogenesis of cardiovascular diseases, including myocardial infarction, ischaemia-reperfusion injury, atherosclerosis, hypertension and heart failure. In this Review, we outline the current understanding of the major factors regulating BCAA abundance and metabolic fate, highlight molecular mechanisms connecting impaired BCAA homeostasis to cardiovascular disease, discuss the epidemiological evidence connecting BCAAs with various cardiovascular disease states and identify current knowledge gaps requiring further investigation.

Fig. 1 |. Major sources and sites of BCAA supply and utilization.

a | Branched-chain amino acids (BCAAs) — isoleucine, leucine and valine — are essential amino acids. The circulating pool of BCAAs is derived from the diet and proteolysis, with a smaller contribution from de novo synthesis by the gut microbiota. Circulating BCAAs are used for protein synthesis or are metabolized. BCAA are imported into the mitochondria by the mitochondrial BCAA carrier, SLC25a44. The first two steps in the BCAA catabolic pathway, mediated by the branched-chain amino transferase (BCAT) and the branched-chain α-keto acid dehydrogenase (BCKDH) enzymes, are shared for all three BCAAs. The catabolic pathway terminates at the tricarboxylic acid (TCA) cycle, but also generates important metabolic intermediates, such as the valine metabolite 3-hydroxyisobutyrate (3-HIB) and the monomethyl branched-chain fatty acids (mmBCFAs), which contribute to intracellular and paracrine signalling. b | Major sites of BCAA incorporation into protein. c | Major sites of BCAA metabolism. α-KG, α-ketoglutarate; BAT, brown adipose tissue; BCKA, branched-chain α-keto acid.

Fig. 2 |. Potential mechanisms connecting dysregulated BCAA metabolism with CVD.

a | In heart failure, the central circadian regulator of branched-chain amino acid (BCAA) metabolism, Krüppel-like factor 15 (KLF15), is downregulated via a mechanism involving transforming growth factor-β-activated kinase 1 (TAK1) and p38 mitogen-activated protein kinase (MAPK) signalling. This leads to decreased expression of BCAA metabolic enzymes, including mitochondrial BCAA aminotransferase (BCAT2), branched-chain α-keto acid dehydrogenase (BCKDH) and mitochondrial protein phosphatase 1K (PPM1K) and accumulation of BCAAs and branched-chain α-keto acids (BCKAs) in the heart. Cardiac injury also potentially impairs BCAA metabolism in peripheral tissues, resulting in increased circulating BCAA and BCKA levels, and therefore increased delivery of BCAAs and BCKAs to the heart. The BCAA leucine promotes activation of serine/threonine-protein kinase mechanistic target of rapamycin (mTOR) in the heart, which blunts autophagy via serine/threonine protein kinase ULK1 (ULK1), promotes insulin resistance via serine phosphorylation of the insulin receptor substrate 1 mediated by ribosomal protein S6 kinase (S6K) and stimulates protein synthesis by phosphorylation of the translational repressor 4E-B P1. BCKAs also lead to increased phosphorylation of 4E-B P1 and induce the MEK–ERK mitogen-activated protein kinase signalling pathway, which promotes protein synthesis. Moreover, exposure to BCKAs impairs mitochondrial complex I activity in the heart, resulting in superoxide generation and oxidative stress. b | In ischaemia–reperfusion injury, whole-body deletion of Ppm1k in mice results in the accumulation of circulating and cardiac BCAAs and BCKAs. This accumulation leads to inhibition of glucose transport and oxidation via decreased O-linked N-acetylglucosaminylation (Glc) of pyruvate dehydrogenase (PDH), and worsened ischaemic injury. c | In animal models of obesity and insulin resistance, BCAA accumulation decreases fatty acid oxidation and increases triglyceride stores. Exposure of the heart to concentrations of BCKAs observed in obesity and type 2 diabetes mellitus (T2DM) inhibits AKT and PDH, resulting in impaired fuel selection. Whether these changes in substrate utilization result in cardiac dysfunction remains to be determined. It is also uncertain whether cardiac-intrinsic changes elicit alterations in BCAA metabolism in other tissues, such as the liver, skeletal muscle or adipose tissue. d | BCAAs impair vascular relaxation in an mTOR-dependent manner that involves reactive oxygen species (ROS) generation. BCAA oxidation in platelets promotes thrombosis by stimulating the propionylation of tropomodulin 3, which leads to platelet activation. The valine-derived metabolite 3-hydroxybutyrate (3-H IB), has been shown to increase transendothelial lipid transport dependent on solute carrier family 27 member 3 (FATP3) and long-chain fatty acid transport protein 4 (FATP4). Whether this BCAA–lipid interplay contributes to atherosclerosis remains to be determined. Dashed arrows in the figure depict pathways that are uncertain. BDK, branched-chain keto acid dehydrogenase kinase; HBP, hexosamine biosynthetic pathway; KIV, α-ketoisovalerate; MI, myocardial infarction.