Elevated pulmonary arterial pressure in Zucker diabetic fatty rats
Open Access
- 28 January 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 14 (1), e0211281
- https://doi.org/10.1371/journal.pone.0211281
Abstract
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.Funding Information
- Ministerio de Economía y Competitividad (SAF2016-77222-R)
- Ministerio de Economía y Competitividad (AGL2015–67087-R)
- Instituto de Salud Carlos III (PI15/01100)
This publication has 40 references indexed in Scilit:
- Pulmonary arterial dysfunction in insulin resistant obese Zucker ratsRespiratory Research, 2011
- Diabetes Mellitus and Risk of Stroke and Its Subtypes Among JapaneseStroke, 2011
- Genetic and Evolutionary Analyses of the Human Bone Morphogenetic Protein Receptor 2 (BMPR2) in the Pathophysiology of ObesityPLOS ONE, 2011
- Effects of Sitagliptin Treatment on Dysmetabolism, Inflammation, and Oxidative Stress in an Animal Model of Type 2 Diabetes (ZDF Rat)Mediators of Inflammation, 2010
- Association of the Metabolic Syndrome With Pulmonary Venous HypertensionSocial psychiatry. Sozialpsychiatrie. Psychiatrie sociale, 2009
- The MIQE Guidelines: Minimum Information for Publication of Quantitative Real-Time PCR ExperimentsClinical Chemistry, 2009
- Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in miceRespiratory Research, 2009
- Insulin resistance in pulmonary arterial hypertensionEuropean Respiratory Journal, 2008
- Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertensionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2008
- The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris.Journal of the American College of Cardiology, 1978