Hypoxia‐induced pulmonary hypertension in type 2 diabetic mice

Abstract

Hypoxia-induced pulmonary hypertension (HPH) is a progressive disease that is mainly caused by chronic exposure to high altitude, chronic obstructive lung disease, and obstructive sleep apnea. The increased pulmonary vascular resistance and increased pulmonary arterial pressure result in increased right ventricular afterload, leading to right heart failure and increased morbidity. There are several clinical reports suggesting a link between PH and diabetes, insulin resistance, or obesity; however, it is unclear whether HPH is associated with diabetes as a progressive complication in diabetes. The major goal of this study is to examine the effect of diabetic “preconditioning” or priming effect on the progression of HPH and define the molecular mechanisms that explain the link between diabetes and HPH. Our data show that HPH is significantly enhanced in diabetic mice, while endothelium-dependent relaxation in pulmonary arteries is significantly attenuated in chronically hypoxic diabetic mice (DH). In addition, we demonstrate that mouse pulmonary endothelial cells (MPECs) isolated from DH mice exhibit a significant increase in mitochondrial reactive oxygen species (ROS) concentration and decreased SOD2 protein expression. Finally, scavenging mitochondrial ROS by mitoTempol restores endothelium-dependent relaxation in pulmonary arteries that is attenuated in DH mice. These data suggest that excessive mitochondrial ROS production in diabetic MPECs leads to the development of severe HPH in diabetic mice exposed to hypoxia.

Pulmonary vascular dysfunction in metabolic syndrome

“…In contrast, we found that both endothelium‐dependent and independent relaxation in PAs was not altered in T2D mice compared to the control (Pan et al . ). These contrasting results might be due to different diabetic models (i.e.…”

“…() showed decreased vascular density in the lung of adult STZ‐induced T1D rats, whereas we have demonstrated a significant increase in vascular density in the lungs of T2D mice (both inducible T2D mice and genetically modified T2D model, KK mice; Pan et al . ). Although we could not find a report on pulmonary vascular density in diabetic patients, there is a report indicating increased pulmonary blood volume and flow in the lung of diabetic patients (Kuziemski et al .…”

“…Furthermore, 4 weeks of hypoxic exposure increased RVSP in T2D mice more than in the controls exposed to hypoxia, suggesting that diabetic mice are more susceptible to hypoxia (Pan et al . ). The increased sensitivity to hypoxia was due, at least in part, to increased mitochondrial ROS generation, decreased superoxide dismutase subtype 2 (SOD2, a SOD expressed in the mitochondria) in diabetic pulmonary ECs, and subsequent attenuation of EDR in pulmonary artery of diabetic mice.…”

Associations between diabetes mellitus and pulmonary hypertension in chronic respiratory disease patients

“…Pan et al reported that elevation of right ventricular pressure due to hypoxia exposure was more pronounced in DM model mice than in their control group, and that increased production of reactive oxygen species and decreased superoxide dismutase were found in the pulmonary arterial endothelial cells of DM mice exposed to hypoxia [ 19 ]. Moral-Sanz et al also reported that hypoxia and DM independently induce pulmonary arterial remodeling and downregulate bone morphogenic protein receptor type 2 [ 20 ].…”

Comparison of Pulmonary and Systemic NO‐ and PGI2‐Dependent Endothelial Function in Diabetic Mice

“…Nonenzymatic nitration may have less significance in the diabetic lungs as compared to systemic circulation. Therefore, despite locally increased ROS generation in pulmonary vessels [ 16 , 37 , 71 ], in the whole lungs, ROS may not play such an important role in pulmonary circulation of the db/db mice as compared to systemic endothelium.…”