Obesity, Hypertension, and Cardiac Dysfunction: Novel Roles of Immunometabolism in Macrophage Activation and Inflammation

Abstract

Obesity and hypertension, which often coexist, are major risk factors for heart failure and are characterized by chronic, low-grade inflammation, which promotes adverse cardiac remodeling. While macrophages play a key role in cardiac remodeling, dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypes promotes excessive inflammation and cardiac injury. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation has been implicated in macrophage polarization. M1 macrophages primarily rely on glycolysis, whereas M2 macrophages rely on the tricarboxylic acid cycle and oxidative phosphorylation; thus, factors that affect macrophage metabolism may disrupt M1/M2 homeostasis and exacerbate inflammation. The mechanisms by which obesity and hypertension may synergistically induce macrophage metabolic dysfunction, particularly during cardiac remodeling, are not fully understood. We propose that obesity and hypertension induce M1 macrophage polarization via mechanisms that directly target macrophage metabolism, including changes in circulating glucose and fatty acid substrates, lipotoxicity, and tissue hypoxia. We discuss canonical and novel proinflammatory roles of macrophages during obesity-hypertension-induced cardiac injury, including diastolic dysfunction and impaired calcium handling. Finally, we discuss the current status of potential therapies to target macrophage metabolism during heart failure, including antidiabetic therapies, anti-inflammatory therapies, and novel immunometabolic agents.

Keywords: heart failure; inflammation; metabolic syndrome; metabolism; mitochondria; myocardium.

Figure 1.. Mechanisms of pro-inflammatory M1 macrophage polarization over the obesity-HTN disease spectrum.

Obesity and its associated complications promote inflammation and macrophage activation, which in turn exacerbates later complications of obesity including SNS/RAAS activation, vascular injury, and heart failure.

Figure 2.. Mechanisms of macrophage-mediated cardiac remodeling.

During cardiac injury and remodeling, macrophages secrete pro-inflammatory cytokines that impair myocyte systolic and diastolic function, activate nearby fibroblasts to promote fibrosis, and inhibit growth of neighboring endothelial cells to impair angiogenesis and neovascularization.

Figure 3.. Role of macrophages and inflammation during the transition to decompensated HF.

In healthy individuals, the heart is populated sparsely with quiescent resident macrophages (blue). During compensatory hypertrophy, there are increased circulating pro-inflammatory monocytes and cytokines, but no changes in cardiac macrophage numbers. When decompensation occurs, circulating levels of pro-inflammatory monocytes and cytokines are further increased, and circulating monocytes begin infiltrating the injured heart.

Figure 4.. Intracellular mechanisms of M1 macrophage metabolic reprogramming during metabolic syndrome.

During obesity-HTN, macrophages sense increases in extracellular glucose, pro-inflammatory fatty acids, hypoxia, and neurohormonal factors, leading to activation of pro-inflammatory NF-κB and HIF-1α pathways, which promote glycolytic and pro-inflammatory gene expression, leading to an M1 phenotype. Glycolysis supports activation of the pentose phosphate pathway (PPP), which generates NADPH to support pro-inflammatory prostaglandin/leukotriene synthesis. Pyruvate entry into the mitochondria is also reduced, leading to a truncated tricarboxylic acid cycle that leads to accumulation of succinate, which supports HIF-1α activation of pro-inflammatory/glycolytic gene expression. Conversely, the anti-inflammatory PPARγ-PGC1β axis, which promotes OXPHOS, is decreased during obesity due to decreases in anti-inflammatory fatty acids such as unsaturated/omega-3 fatty acids. Blue arrows indicate activation, orange arrows indicate inhibition. ACh—acetylcholine, Ang II—angiotensin II, ETC—electron transport chain, FAO—fatty acid oxidation, FAS—fatty acid synthesis, GLUT1—glucose transporter 1, HIF-1α—hypoxia inducible factor-1 alpha, LTNs—leukotrienes, NADPH—nicotinamide adenine dinucleotide phosphate, NE—norepinephrine, NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells, PGs—prostaglandins, PDH—pyruvate dehydrogenase, PDK1—pyruvate dehydrogenase kinase 1, PGC1β—PPAR gamma coactivator 1 beta, PPARγ—peroxisome proliferator activated receptor gamma, PPP—pentose phosphate pathway, ROS—reactive oxygen species, TCA—tricarboxylic acid cycle.