Pulmonary vascular effect of insulin in a rodent model of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is associated with metabolic derangements including insulin resistance, although their effects on the cardiopulmonary disease are unclear. We hypothesized that insulin resistance promotes pulmonary hypertension (PH) development and mutations in type 2 bone morphogenetic protein receptor (BMPR2) cause cellular insulin resistance. Using a BMPR2 transgenic murine model of PAH and two models of inducible diabetes mellitus, we explored the impact of hyperglycemia and/or hyperinsulinemia on development and severity of PH. We assessed insulin signaling and insulin-mediated glucose uptake in human endothelial cells with and without mutations in BMPR2. PH developed in control mice fed a Western diet and PH in BMPR2 mutant mice was increased by Western diet. Pulmonary artery pressure correlated strongly with fasting plasma insulin but not glucose. Reactive oxygen species were increased in lungs of insulin-resistant animals. BMPR2 mutation impaired insulin-mediated endothelial glucose uptake via reduced glucose transporter translocation despite intact insulin signaling. Experimental hyperinsulinemia is strongly associated with PH in both control and BMPR2-mutant mice, though to a greater degree in those with BMPR2 mutation. Human pulmonary endothelial cells with BMPR2 mutation have evidence of reduced glucose uptake due to impaired glucose transporter translocation. These experiments support a role for hyperinsulinemia in pulmonary vascular disease.

Adverse physiologic effects of Western diet on right ventricular structure and function: role of lipid accumulation and metabolic therapy

“…5 Our group recently showed that the pulmonary vascular response to WD is driven by hyperinsulinemia rather than hyperglycemia. 6 Although the focus of the present work was to assess the effects of WD on RV structure and function, we observed a 39% increase in invasively measured RVSP in wild-type mouse without any other PH-promoting intervention. Moreover, this WD-induced increase in RVSP was reduced with metformin therapy.…”

Human PAH is characterized by a pattern of lipid-related insulin resistance

“…An imbalance in prostacyclin production through arachidonic acid metabolism is long described in PAH and may be at least in part affected by alterations in lipid metabolism related to IR (38). As prior work by our group and others has suggested that IR is causal in the development of pulmonary vascular disease (10,11,13,14), we sought to define biological relevance of our lipid-related findings. We explored lipoprotein-related inflammation as a link between our plasma findings and pulmonary vascular disease.…”

“…Thus, lipoprotein IR is indicated by elevated VLDL (triglyceride)/HDL cholesterol ratio. IR is increasingly implicated in PAH; several rodent models of IR such as the ApoE -/mouse have pulmonary hypertension (10)(11)(12) and IR is an early feature of a transgenic rodent model of heritable PAH with BMPR2 mutation (13,14). In addition to atherogenic dyslipidemia, IR in the lipid axis is characterized by abnormal skeletal muscle lipid deposition (15)(16)(17).…”

Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension

“…Further, even rodents without BMPR2 mutation develop mild elevations in pulmonary arterial pressure. In both the BMPR2 R899X mice and wild type controls, pulmonary arterial pressure was directly correlated with plasma insulin levels but not plasma glucose levels (Trammell et al, ). These data provide further evidence of a causal relationship between insulin resistance and PAH development.…”