Vascular hypertrophy and hypertension caused by transgenic overexpression of profilin 1.
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.
Moustafa-Bayoumi
Moustafa
M
Department of Kinesiology and Health Promotion, California State Polytechnic University, Pomona, CA 91768, USA.
Alhaj
Mazin A
MA
El-Sayed
Osama
O
Wisel
Sheik
S
Chotani
Maqsood A
MA
Abouelnaga
Zeinb A
ZA
Hassona
Mohamed D H
MD
Rigatto
Katya
K
Morris
Mariana
M
Nuovo
Gerard
G
Zweier
Jay L
JL
Goldschmidt-Clermont
Pascal
P
Hassanain
Hamdy
H
D000199:Actins / Q000737:chemistry; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001021:Aortic Valve / Q000166:cytology; D001794:Blood Pressure; D005786:Gene Expression Regulation; D006973:Hypertension / Q000235:genetics*; D006984:Hypertrophy / Q000235:genetics*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D051304:Profilins / Q000096:biosynthesis* / Q000235:genetics*; D015398:Signal Transduction
D000199:Actins; D051304:Profilins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3