Date Published: January 28, 2019
Publisher: Public Library of Science
Author(s): Daniel Morales-Cano, Maria Callejo, Bianca Barreira, Gema Mondejar-Parreño, Sergio Esquivel-Ruiz, Sonia Ramos, María Ángeles Martín, Angel Cogolludo, Laura Moreno, Francisco Perez-Vizcaino, Michael Bader.
Diabetes is a very strong predictor of chronic systemic vascular diseases and acute cardiovascular events. Recently, associations between metabolic disorders and pulmonary hypertension have also been reported in both humans and animal models. In order to get some further insight into the relationship of pulmonary hypertension with obesity, insulin resistance and hyperglycemia, herein we have used the Zucker diabetic fatty rats (ZDF/clr-lepr fa) at 20 weeks fed a standard diet and compared to their lean Zucker littermates (ZL). ZDF rats were obese, had elevated plasma glucose levels and insulin resistance, i.e. a clinically relevant model of type 2 diabetes. They presented elevated systolic, diastolic and mean pulmonary arterial pressures and a parallel increase in the Fulton index. Systemic arterial pressures were also increased but the left ventricle plus septum weight was similar in both groups and the heart rate was reduced. Wall media thickening was observed in the small pulmonary arteries from the ZDF rats. Isolated pulmonary arteries mounted in a wire myograph showed similar vasoconstrictor responses to phenylephrine and 5-HT and similar responses to the endothelium-dependent vasodilator acetylcholine. However, the iNOS inhibitor 1400W enhanced the vasoconstrictor responses in ZDF but not in ZL rats. The protein expression of eNOS and iNOS was not significantly different in the lungs of the two groups. The lung expression of Bmpr2 mRNA was downregulated. However, the mRNA expression of Kcna5, Kcnk3, Kcnq1, Kcnq4 or Kcnq5, which encode for the potassium channels Kv1.5, TASK-1, Kv7.1, Kv7.4 and Kv7.5, respectively, was similar in ZL and ZDF rats. In conclusion, ZDF rats show increased pulmonary arterial pressure, right ventricular hypertrophy, pulmonary arterial medial thickening and downregulated lung Bmpr2 despite leptin resistance. These changes were mild but are consistent with the view that diabetes is a risk factor for pulmonary hypertension.
Pulmonary hypertension (PH) is characterized by an increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance determined by right heart catheterization at rest . It is classified into 5 groups according to its origin: 1) pulmonary arterial hypertension (PAH), 2) PH hypertension associated with left heart disease, 3) PH associated with lung diseases and hypoxia, 4) PH associated to chronic thromboembolism (CTEPH), and 5) PH of unknown origin or multifactorial . With the exception of idiopathic PAH, in all groups and subgroups of PH there is a known factor, such as a mutation, infection, hypoxia, drugs, embolism or other diseases, that is associated with the development of the disease. However, none of these factors by itself is sufficient to trigger the disease . The clinical risk factors that predict the development of PH in patients at risk, i.e. the so called “second hits”, have not yet been fully identified.
The results of the present study indicate that when compared to their lean littermates, ZDF rats show elevated PAP, RV hypertrophy, remodeling of the vessel structure and altered pattern of lung gene expression. All these changes were mild. Consistent with previous reports [26, 27] these animals also showed elevated systemic arterial pressure. However, there was no apparent change in the responses to vasoconstrictors in the PA, except that the responses were mildly potentiated in ZDF rats by the iNOS inhibitor 1400W. In addition, ZDF rats did not show apparent pulmonary endothelial dysfunction as indicated by a response to the endothelial-dependent vasodilator acetylcholine similar to that of ZL rats.
Previous models of hyperglycemia or obesity with or without hyperinsulinemia have shown different anatomic or functional PA alterations. These animals developed increased PAP and RV hypertrophy only when combined with moderate altitude or normobaric hypoxia. Herein, we report that the ZDF rat which develops frank type 2 diabetes with hyperglycemia, hyperinsulinemia and obesity at 20 weeks of age shows elevated PAP, PA remodeling, RV hypertrophy and bmpr2 downregulation making this animal a suitable model to study the association between glucose and lipid metabolic dysregulation and pulmonary hypertension. The present data also support the continuous growing evidence that diabetes is a risk factor for PH.