Vascular hypertrophy and hypertension caused by transgenic overexpression of profilin 1.

Abstract

We have overexpressed either the cDNA of human profilin 1 or expressed the mutant (88R/L) in the blood vessels of transgenic FVB/N mice. Reverse transcription-PCR indicated selective overexpression of profilin 1 and 88R/L in vascular smooth muscle cells. Polyproline binding showed increased profilin 1 and 88R/L proteins in transgenic mice compared with control (~30%, p < 0.05). Rhodamine-phalloidin staining revealed increase stress fiber formation in vascular smooth muscle cells of profilin 1 compared with 88R/L and control. Hematoxylin and eosin staining showed clear signs of vascular hypertrophy in the aorta of profilin 1 mice versus 88R/L and control. However, there were no differences between 88R/L and control mice. Western blotting confirmed the activation of the hypertrophic signaling cascades in aortas of profilin 1 mice. Phospho-ERK1/2 was significantly higher in profilin 1 than 88R/L and control (512.3 and 361.7%, respectively, p < 0.05). Profilin 1 mice had significant increases in phospho-JNK as compared with 88R/L and control (371.4 and 346%, respectively, p < 0.05). However, there were no differences between 88R/L and control mice in both kinases. There was a significant increase in ROCK II kinase in the aorta of profilin 1 mice compared with controls (>400%, p < 0.05). Tail cuff and circadian monitoring of blood pressure showed significant increases in systolic and mean arterial blood pressures of profilin 1 mice starting at age 6 months compared with controls (~25 mm Hg, p < 0.05). These results suggest that increased actin polymerization in blood vessels triggers activation of the hypertrophic signaling cascades and results in elevation of blood pressure at advanced age.

• Authors: Moustafa Moustafa-Bayoumi, Mazin A Alhaj, Osama El-Sayed, Sheik Wisel, Maqsood A Chotani, Zeinb A Abouelnaga, Mohamed D H Hassona, Katya Rigatto, Mariana Morris, Gerard Nuovo, Jay L Zweier, Pascal Goldschmidt-Clermont, Hamdy Hassanain
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 52 Pg. 37632-9 (Dec 28 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17942408 (Publication Type: Journal Article)

Chemical References

• Actins
• Profilins
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Actins (chemistry)
• Animals
• Aorta (metabolism)
• Aortic Valve (cytology)
• Blood Pressure
• Gene Expression Regulation
• Hypertension (genetics)
• Hypertrophy (genetics)
• MAP Kinase Signaling System
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Models, Biological
• Myocytes, Smooth Muscle (cytology)
• Profilins (biosynthesis, genetics)
• Signal Transduction