Evidence for the involvement of matrix metalloproteinases in the cardiovascular effects produced by nicotine.
Nicotine plays a role in smoking-associated cardiovascular diseases, and may upregulate matrix metalloproteinase (MMP)-2 and MMP-9. We examined whether nicotine induces the release of MMP-2 and MMP-9 by rat smooth muscle cells (SMC), and whether doxycycline (non-selective MMP inhibitor) inhibits the vascular effects produced by nicotine. SMC were incubated with nicotine 0, 50, and 150 nM for 48 h. MMP-2 and MMP-9 levels in the cell supernatants were determined by gelatin zymography. The acute changes in mean arterial pressure caused by nicotine 2 micromol/kg (or saline) were assessed in rats pretreated with doxycycline (or saline). We also examined whether doxcycline (30 mg/Kg, i.p., daily) modifies the effects of nicotine (10mg/kg/day; 4 weeks) on the endothelium-dependent relaxations of rat aortic rings. Aortic MMP-2 levels were assessed by gelatin zymography. Aortic gelatinolytic activity was assessed using a gelatinolytic activity kit. MMP-2 and MMP-9 levels increased in the supernatant of SMC cells incubated with nicotine 150 nM (P<0.05) but not with 50 nM. Nicotine (2 micromol/kg) produced lower increases in the mean arterial pressure in rats pretreated with doxycycline than those found in rats pretreated with saline (26+/-4 vs. 37+/-4 mm Hg, respectively; P<0.05). Nicotine impaired of the endothelium-dependent responses to acetylcholine, and treatment with doxycycline increased the potency (pD2) by approximately 25% (P<0.05). While we found no significant differences in aortic MMP-2 levels, nicotine significantly increased gelatinolytic activity (P<0.05). These findings suggest that nicotine produces cardiovascular effects involving MMPs. It is possible that MMPs inhibition may counteract the effects produced by nicotine.
Jacob-Ferreira
Anna L B
AL
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
Palei
Ana C T
AC
Cau
Stefany B
SB
Moreno
Heitor
H
Martinez
Marcio L L
ML
Izidoro-Toledo
Tatiane C
TC
Gerlach
Raquel F
RF
Tanus-Santos
Jose E
JE
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology; D002319:Cardiovascular System / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D002460:Cell Line; D004318:Doxycycline / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000633:toxicity*; D051381:Rats; D013997:Time Factors
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009538:Nicotine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline