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Korean Circ J. 2003 Feb;33(2):130-138. Korean. In Vitro.
Kim D , Hong BK , Kwon HM , Kim DY , Cho YH , Yoon SJ , Kim HS , Yan C .
Cardiology Division, Yonsei University College of Medicine, Seoul, Korea.
Center for Cardiovascular Research, University of Rochester, NY, US.

BACKGROUND AND OBJECTIVES: Angiotensin II (Ang II) opposes the actions of nitric oxide (NO). A balance between Ang II and NO is critical for the maintenance of normal vessel tone, and is dependent on the intracellular cGMP level. We examined the effect of Ang II treatment on cGMP-hydrolyzing phosphodiesterases (PDEs), such as PDE1 and PDE5, the two major cGMP-hydrolyzing PDEs present in rat aortic vascular smooth muscle cells (VSMCs). We also investigated whether the Ang II signaling pathway affects the expression of the cGMP-hydrolyzing PDEs gene. MATERIALS AND MEDHODS: VSMCs from Sprague-Dawley rats were incubated. Relative quantitative RT-PCR was performed for quantitation of PDE1A1, PDE5A1 mRNA expression a following in vitro Ang II treatment, and also done after pretreatment with inhibitors of the Ang II type1 (AT1) receptor, protein kinase C (PKC), mitogen activated protein kinase kinase (MEK) 1/2 and janus kinase 2 (JAK2) to investigate the effect of the Ang II signaling pathway on PDE1A1, PDE5A1 gene expression. Western blot analyses were performed to evaluate the changes of PDE1A1 and PDE5A1 protein level following treatment with Ang II. RESULTS: Ang II (400 nM) increased the PDE1A1 and the PDE5A1 mRNA expression by 2.4 and 2.3-fold, respectively, 1 hour after treatment. Ang II also increased the protein level 2 hours after treatment. Inductions of PDE1A1 and PDE5A1 mRNA were blocked by the AT1 receptor inhibitors, PKC, MEK 1/2 and JAK2. CONCLUSION: In vitro Ang II treatment upregulates the PDE1A1, PDE5A1 gene expressions and the protein levels. The PKC, MEK1/2 and JAK2 signaling pathways were essential for the Ang II-mediated PDEs gene regulation. These findings may suggest that Ang II antagonizes NO actions through the upregulation of cGMP-hydrolyzing PDEs gene expressions.

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