Pulmonary Arterial Hypertension and Insulin Resistance

Abstract

The clinical recognition of pulmonary arterial hypertension (PAH) is increasing, and with recent therapeutic advances, short-term survival has improved. In spite of these advances, however, PAH remains a disease with substantial morbidity and long-term mortality. The pathogenesis of PAH involves a complex interaction of local and distant cytokines, growth factors, co-factors, and transcription factors occurring in the right genetic and environmental setting. These factors ultimately lead to the detrimental changes in vascular anatomy and function seen in PAH patients. An important association between obesity/insulin resistance and PAH has recently been identified. Both conditions occur in the presence of a chronic low-grade inflammatory state, and although it is unlikely that a single pathway is solely responsible for the observed association, deficiencies in adiponectin, apolipoprotein E (ApoE) and peroxisome proliferator-activator receptor gamma (PPAR-γ) activity likely play a prominent role. Although incompletely understood, it is clear that further investigation is warranted and the role of weight loss and improved glycemic control in the treatment of at-risk patients with PAH and obesity should be determined.

Keywords: Insulin resistance; Pulmonary arterial hypertension.

Figure 1

The key pathological mechanisms underlying vascular changes in pulmonary hypertension (PH). Potential new therapies for PH are also indicated. AEC: Alveolar Epithelial Cell; vWF: von Willebrand Factor; TXA2: Thromboxane A2; NO: Nitric oxide; EPC: Endothelial Progenitor Cell; ET-1: Endothelin-1; PGI2: Prostaglandin I2; sGC: Soluble Guanylate Cyclase; cGMP: Cyclic Guanosine Monophosphate; 5-HT: 5-hydroxytryptamine; VEGF: Vascular Endothelial Growth Factor; bFGF: Basic Fibroblast Growth Factor; TGF-a: Transforming Growth Factor-a; PDGF: Platelet-derived Growth Factor; HGF: Hepatocyte Growth Factor; PPARc: Peroxisome Proliferator-Activated Receptor-c;STAT3: Signal Transducer and Activator of Transcription 3; NFAT: Nuclear Factor of Activated T-cells; MCP-1: Monocyte Chemoattractant Protein-1; TNF: Tumour Necrosis Factor; IL: Interleukin; FKN: Fractalkine; CCL: Chemokine Ligand; cAMP: Cyclic Adenosine Monophosphate.

Figure 2

Potential pathways underlying the association between obesity-induced insulin resistance and pulmonary arterial hypertension. ET-1: Endothelin-1; ADMA: Asymmetric Dimethyl-Arginine; NOS: nNitric Oxide Synthase; PDGFR-β: Platelet-derived Growth Factor Receptor Beta; MAPK: Mitogen-activated Protein Kinase; AMPK: AMP Activated Protein Kinase; mTOR: Mammalian Target of Rapamycin; NFκB: Nuclear Factor Kappa-light-chain-Enhancer of Activated B cells; ApoE: Apolipoprotein E.