Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms

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Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms John A. Curci, MD, Dongli Mao, MD, Diane G. Bohner, RN, Brent T. Allen, MD, Brian G. Rubin, MD, Jeffrey M. Reilly, MD, Gregorio A. Sicard, MD, Robert W. Thompson, MD Journal of Vascular Surgery Volume 31, Issue 2, Pages 325-342 (February 2000) DOI: 10.1016/S0741-5214(00)90163-0 Copyright © 2000 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 1 Substrate zymography. Total protein was extracted from the aneurysm wall tissue of patients treated with doxycycline (n = 5), untreated control patients (n = 5), and two healthy aortas. Equivalent amounts of protein (10 ug per lane) were electrophoretically separated on a 10% polyacrylamide gel containing 1 mg/mL gelatin. A, Gelatinase activity was identified by clear bands on a dark background after staining with Coomassie Blue (representative of four separate experiments). B, The mean density of bands corresponding to proMMP-9 (92 kDa), active MMP-9 (88 kDa), proMMP-2 (72 kDa), and active MMP-2 (68 kDa) were measured. There was no difference between groups in total matrix metalloproteinase activity for either MMP-2 or MMP-9 (not shown). The activated fraction of MMP-2 was slightly decreased in samples from patients with abdominal aortic aneurysms treated with doxycycline, compared with those from untreated control patients (P <.05), but there was no difference in the activated fraction of MMP-9. NS, not significant. Journal of Vascular Surgery 2000 31, 325-342DOI: (10.1016/S0741-5214(00)90163-0) Copyright © 2000 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 2 Immunoblotting for MMP-9 in human aortic tissue extracts. Total protein was extracted from the aortic wall tissue of patients treated with doxycycline (n = 6), untreated control patients (n = 4), and two healthy aortas. Equivalent amounts of protein (100 ug per lane) were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes. A, Blots incubated with a monoclonal antibody to human MMP-9 demonstrated a single band migrating at 92 kDa. B, By using band densitometry, samples from untreated patients with abdominal aortic aneurysms contained significantly more MMP-9 protein than those from healthy aortas (P <.05). Samples from patients with an abdominal aortic aneurysm treated with doxycycline exhibited a significant decrease in the amount of detectable MMP-9 protein, compared with those from untreated patients with an abdominal aortic aneurysm (P <.05). There was no significant difference between the amount of MMP-9 in samples from the doxycycline-treated group and those from normal aortas. NS, not significant. Journal of Vascular Surgery 2000 31, 325-342DOI: (10.1016/S0741-5214(00)90163-0) Copyright © 2000 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 3 Reverse transcription-polymerase chain reaction and Southern blot analysis of MMP-9 and MMP-2 RNA in human aneurysm tissue. Total RNA was extracted from aneurysm wall tissue of patients treated with doxycycline and untreated control patients, then amplified by reverse transcription-polymerase chain reaction using primer pairs specific for MMP-9, MMP-2, and β-actin. A, Reverse transcription-polymerase chain reaction products were confirmed by means of Southern blot with specific probes within the amplified sequence. Although there was some variation in MMP-9 and MMP-2 production between specimens, there was a recognizable decrease in the expression of MMP-9 between samples from patients treated with doxycycline and untreated control patients. B, Densitometric analysis of MMP-9 and MMP-2 relative to β-actin. There was a significant decrease in the amount of MMP-9 messenger RNA in samples from the doxycycline-treated group, compared with untreated controls (P <.05). The difference between groups for MMP-2 messenger RNA was not significant. NS, not significant. C, Densitometric measurements of MMP-9 messenger RNA for individual specimens shown in A. Five of the seven specimens from untreated patients with abdominal aortic aneurysms had normalized densities greater than or equal to 7 (horizontal line) , whereas none of the eight specimens from patients treated with doxycycline had normalized densities greater than this value (P <.01; χ2 analysis). D, Densitometric measurements of MMP-2 messenger RNA for the same samples shown in C. There was no detectable trend differentiating the two groups. Journal of Vascular Surgery 2000 31, 325-342DOI: (10.1016/S0741-5214(00)90163-0) Copyright © 2000 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 4 Representative results of competitive reverse transcription-polymerase chain reaction analysis for MMP-9. Native complementary DNA prepared by reverse transcription from AAA tissue was amplified in a series of reactions containing increasing amounts of an MMP-9 competitor complementary DNA, which competes with the native complementary DNA for a fixed quantity of oligonucleotide primers. A, By design, the two products of polymerase chain reaction amplification (at least 100 base pair different) can be distinguished by size after agarose electrophoresis. B, The amount of competitor added (in moles) was plotted against the density ratio of the two bands by using a log/log scale. After linear regression to ensure a correlation coefficient less than –0.90, the x-intercept of the plotted data was determined to be the point at which the (known) amount of competitor and the (unknown) amount of native complementary DNA are equivalent. For accurate comparisons, the amount of MMP-9 complementary DNA in each sample was normalized to the amount of β-actin measured in a parallel series of competitive reactions, and expressed as an mol/mol ratio. Journal of Vascular Surgery 2000 31, 325-342DOI: (10.1016/S0741-5214(00)90163-0) Copyright © 2000 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 5 Summary of competitive reverse transcription-polymerase chain reaction analysis for MMP-9 in abdominal aortic aneurysm tissue. MMP-9 messenger RNA in aneurysm tissue was quantified by means of competitive reverse transcription-polymerase chain reaction as shown in Fig 4, by using total RNA obtained from five patients treated with doxycycline and four untreated control patients. Data were expressed as a molar ratio of MMP-9 to β-actin. Treatment with doxycycline was associated with a 5.5-fold (81.9%) reduction in the expression of MMP-9, compared with the untreated control group (P <.04; Student t test). Journal of Vascular Surgery 2000 31, 325-342DOI: (10.1016/S0741-5214(00)90163-0) Copyright © 2000 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions

Fig. 6 Effect of doxycycline on MMP-9 production in phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells. An equivalent number of human THP-1 mononuclear phagocytes were preincubated with either 0, 2.5, 5, 10, or 12 μmol/L doxycycline for 24 hours, then stimulated for 48 hours with 100 nmol/L PMA in the continuing presence of doxycycline. At all concentrations of doxycycline tested, cells exhibited a normal morphologic appearance following PMA stimulation with differentiation to an adherent phenotype (not shown). A, Cellular expression of MMP-9 and β-actin messenger RNA was measured by means of reverse transcription-polymerase chain reaction, with data normalized to β-actin and expressed as a percentage of control (cells not exposed to doxycycline). Doxycycline induced a concentration-dependent inhibition of MMP-9 messenger RNA expression (r = –0.88; P <.05). B, Conditioned media were normalized to total protein concentration and examined by means of Western blot with monoclonal antibodies to human MMP-9. Total immunoreactive MMP-9 was measured by means of densitometry and expressed as a percentage of control. Doxycycline induced a concentration-dependent decrease in the amount of MMP-9 protein secreted into the conditioned medium (r = –0.90; P <.04). C, Equal amounts of conditioned media were examined by means of gelatin zymography. Total gelatinolytic activity attributable to MMP-9 was measured by means of inverse densitometry and expressed as a percentage of control. Doxycycline (not present in the substrate buffer during zymography) induced a concentration-dependent decrease in MMP-9 activity secreted into the conditioned medium (r = –0.95; P <.02). Journal of Vascular Surgery 2000 31, 325-342DOI: (10.1016/S0741-5214(00)90163-0) Copyright © 2000 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter Terms and Conditions