US EPA

2262473 

Journal Article 

Abstract 

The effect of nitric oxide (NO) on cell proliferation in pulmonary hypertension may be mediated by Hyaluronan (HA) 

Aytekin, M; Haserodt, SK; Dweik, RA 

2010 

Yes 

American Journal of Respiratory and Critical Care Medicine
ISSN: 1073-449X
EISSN: 1535-4970 

181 

A6290 

English 

10.1164/ajrccm-conference.2010.181.1_MeetingAbstracts.A6290 

WOS:000208771004649 

is part of a larger document 3452678 Proceedings of the American Thoracic Society 2010 International Conference, May 14-19, 2010, New Orleans

Rationale: We and others have previously shown that nitric oxide (NO) levels are low in patients with idiopathic pulmonary arterial hypertension (IPAH). We have recently demonstrated that IPAH patients also have high levels of Hyaluronan (HA) a large glycosaminoglycan found in the extracellular matrix. Since both NO and HA are known to play roles in smooth muscle proliferation and migration, we hypothesized that NO effects on smooth muscle cell proliferation could be mediated by HA.

Methods: Pulmonary artery smooth muscle cells (PASMCs) isolated from pulmonary arteries from explanted IPAH and control lungs were treated with different amounts of NO and agarose gel HA sizing was performed. PASMCs and Human umbilical vein endothelial cells (HUVECs) plated on a coverslip were subjected to a controlled wound by a pipette tip. The effect of different levels of NO on would closure was evaluated in PASMCs and the effect of different sizes of exogenous HA (4.7, 35, 74, and 2milion kDa) on wound closure was evaluated in HUVECS.

Results: PASMCs exposed to the 10 uM NO (NO donor NOC-18) had the fastest wound closure rates HA [wound closure (arbitrary unit, mean±SD): 0uM NO 32.9±3.9, 10uM NO 17.3±2.0, 500uM NO 63.4±9.8]. Furthermore, Agarose gel HA sizing showed that treatment of IPAH PASMCs with low levels of NO (10 uM) resulted in increased small molecular weight HA production (~100-200 kDa) compared to control PASMCs. High levels of NO (500 uM) produced mostly large molecular weight HA (>1510 kDa) in both IPAH and control PASMCs. Wounded HUVECs treated with small size hyaluronan (35kDa) had increased wound closure compared to HUVECs treated with larger HA [wound closure (arbitrary unit, mean±SD): 4.7kDa 0.34±0.04, 35kDa 0.19±0.09, 74kDa 0.29±0.01, 2million kDa 0.40±0.03].

Conclusion: NO affects the size of hyaluronan differently in IPAH patients than in controls. Furthermore, small HA fragments (35 kDa) HA increase the rate of wound closure in HUVECs. Thus, the small sizes of HA produced by NO in IPAH may play a role in the increase vascular proliferation characteristic of this disease. 

American Thoracic Society 2010 International Conference 

New Orleans, LA 

May 14-19, 2010