Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase.
Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of < 2.5 microm (PM(2.5)) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM(2.5) or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM(2.5) exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM(2.5) exposure along with increased expression of the guanine exchange factors (GEFs) PDZ-RhoGEF and p115 RhoGEF in PM(2.5)-exposed mice. Parallel with increased RhoA activation, PM(2.5) exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM(2.5) potentiates cardiac remodeling in response to ANG II through RhoA/Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution.
Ying
Zhekang
Z
Davis Heart Lung Research Institute, The Ohio State Univ., Rm. 110, 473 W. 12th Ave., Columbus, OH 43210-1252, USA.
Yue
Peibin
P
Xu
Xiaohua
X
Zhong
Mianhua
M
Sun
Qinghua
Q
Mikolaj
Michael
M
Wang
Aixia
A
Brook
Robert D
RD
Chen
Lung Chi
LC
Rajagopalan
Sanjay
S
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001273:Atmosphere Exposure Chambers; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D007260:Infusion Pumps; D019570:Inhalation Exposure; D007274:Injections, Intraperitoneal; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology*; D052638:Particulate Matter / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
D020662:Guanine Nucleotide Exchange Factors; D052638:Particulate Matter; D047428:Protein Kinase Inhibitors; D064067:Rho Guanine Nucleotide Exchange Factors; D000804:Angiotensin II; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003094:Collagen; D054460:rho-Associated Kinases; D053505:Matrix Metalloproteinases, Secreted; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C049347:fasudil