Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

Abstract

The heart has a reduced capacity to generate sufficient energy when failing, resulting in an energy-starved condition with diminished functions. Studies have identified numerous changes in metabolic pathways in the failing heart that result in reduced oxidation of both glucose and fatty acid substrates, defects in mitochondrial functions and oxidative phosphorylation, and inefficient substrate utilization for the ATP that is produced. Recent early-phase clinical studies indicate that inhibitors of fatty acid oxidation and antioxidants that target the mitochondria may improve heart function during failure by increasing compensatory glucose oxidation. Adrenergic receptors (α₁ and β) are a key sympathetic nervous system regulator that controls cardiac function. β-AR blockers are an established treatment for heart failure and α_1A-AR agonists have potential therapeutic benefit. Besides regulating inotropy and chronotropy, α₁- and β-adrenergic receptors also regulate metabolic functions in the heart that underlie many cardiac benefits. This review will highlight recent studies that describe how adrenergic receptor-mediated metabolic pathways may be able to restore cardiac energetics to non-failing levels that may offer promising therapeutic strategies.

Keywords: adrenergic receptor; heart; metabolism; myocyte.

Figure 1

Adrenergic pathways that affect glucose utilization in the cardiac myocyte, showing glycolysis, glucose oxidation inside the mitochondrion, and the alternative pentose phosphate pathway (PPP). AC, adenylate cyclase; ADP, adenosine diphosphate; AMPK, AMP-activated protein kinase; AR, adrenergic receptor; ATP, adenosine triphosphate; CoA, coenzyme A; cAMP, cyclic adenosine monophosphate; FAD, flavin adenine dinucleotide; GLUT, Glucose transporter; IMM, inner mitochondrial membrane; IP3, inositol triphosphate; OMM, outer mitochondrial membrane; PFK, phosphofructokinase; PKC, protein kinase C; PLC, phospholipase C; PPAR, peroxisome proliferator-activated receptor; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle.

Figure 2

Adrenergic Receptor Regulation of Fatty Acid Metabolism in the Cardiac Myocyte. AC, adenylate cyclase; ADP, adenosine diphosphate; AMPK, AMP-activated protein kinase; AR, adrenergic receptor; ATP, adenosine triphosphate; CoA, coenzyme A; cAMP, cyclic adenosine monophosphate; CPT, carnitine palmitoyltransferase; FAD, flavin adenine dinucleotide; FATP1, Fatty acid transport protein 1; FFA, free fatty acid; IMM, inner mitochondrial membrane; NAD, nicotinamide adenine dinucleotide; OMM, outer mitochondrial membrane; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle.