Abstract
Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague-Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down-regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension.
Footnotes
This work was supported by the Ministerio de Ciencia e Innovación [Grants SAF2008-03948, SAF2010-22066-C02-02, AGL2007-66108] and Mutua Madrileña.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179515.
-
ABBREVIATIONS:
- PAH
- pulmonary arterial hypertension
- 5-HT
- 5-hydroxytryptamine (serotonin)
- BMPR2
- bone morphogenetic protein receptor type 2
- BW
- body weight
- COX
- cyclooxygenase
- Emax
- maximal drug effect
- KV
- voltage-gated potassium channel
- LV
- left ventricle
- PA
- pulmonary artery
- S
- septum
- SAP
- systemic arterial pressure
- RV
- right ventricle
- RVSP
- right ventricular systolic pressure
- SOD
- superoxide dismutase
- TXA2
- thromboxane A2
- NS-398
- N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide
- U46619
- (Z)-7-[(1S,3S,4S)-3-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxabicyclo[2.2.1]heptan-2-yl]hept-5-enoic acid
- l-NAME
- Nω-nitro-l-arginine methyl ester
- SC236
- 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide
- TP
- thromboxane prostanoid
- ROS
- reactive oxygen species.
- Received January 17, 2011.
- Accepted April 25, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|