minocycline and Atherosclerosis

Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel. We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.

Topics: Animals; Anti-Inflammatory Agents; Aortitis; Atherosclerosis; Brachiocephalic Trunk; Collagen; Disease Models, Animal; Disease Progression; Inflammation Mediators; Interleukin-6; Lipid Metabolism; Male; Mice, Knockout, ApoE; Minocycline; Necrosis; Plaque, Atherosclerotic; Pravastatin; Time Factors

To investigate whether minocycline could attenuate the expression of extracellular matrix metalloproteinase inducer (CD147) and matrix metalloproteinase (MMP)-9 and enhance stability of atherosclerotic plaques.. Twenty-four New Zealand rabbits underwent balloon-induced endothelial injury of right carotid artery and were fed 1% cholesterol diet for 16 weeks. From week 12 to week 16, the animals were intervened with minocycline (2·5 mg kg(-1) d(-1), group A), atorvastatin (2·5 mg kg(-1) d(-1), group B) or were not treated with drugs (group C). After 16 weeks, all the rabbits were sacrificed by Chinese Russell's viper venom and histamine injection, then serum and right common carotid arteries were collected for biochemical, histological, and reverse transcription polymerase chain reaction (RT-PCR) analysis.. A rabbit model of atherosclerotic vulnerable plaques was established. Minocycline significantly increased the thickness of the plaque fibrous caps and decreased the positive staining area of macrophages in group A. When compared with group C, CD147, and MMP-9 expression in both mRNA and protein level were remarkably reduced in group A and B (P < 0·05). However, there was no significant difference between group A and B. Serum TC and low-density lipoprotein cholesterol (LDL-C) levels were decreased in the Atorvastatin group (P < 0·05), while minocycline had no obvious influence on the serum lipid levels. The incidence of plaque ruptures in group A (14·3%) and group B (14·3%) was lower than that in group C (66·7%, P < 0·05).. Minocycline intervention significantly reduced the activity of CD147, MMP in plaque and histologically enhanced plaque stabilization. Minocycline was equally effective as Atorvastatin.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Atorvastatin; Basigin; Carotid Artery, Common; Cholesterol; Cholesterol, LDL; Heptanoic Acids; Male; Matrix Metalloproteinase 9; Minocycline; Plaque, Atherosclerotic; Pyrroles; Rabbits

Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magnetic resonance imaging (MRI) using an albumin-binding contrast agent, gadofosveset, could monitor the efficacy of minocycline and ebselen in reducing endothelial permeability and atherosclerotic burden in the brachiocephalic artery of high-fat diet (HFD)-fed ApoE-/- mice.. ApoE-/- mice were scanned 12 weeks after commencement of either a normal diet (controls) or an HFD. HFD-fed ApoE-/- mice were either untreated or treated with minocycline or ebselen for 12 weeks. Delayed-enhancement MRI and T1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R1, s(-1)) in untreated HFD-fed ApoE-/- mice (R1 = 3.8 ± 0.52 s(-1)) compared with controls (R1 = 2.15 ± 0.34 s(-1), P < 0.001). Conversely, minocycline-treated (R1 = 2.7 ± 0.17 s(-1), P < 0.001) and ebselen-treated (R1 = 2.7 ± 0.23 s(-1), P < 0.001) ApoE-/- mice showed less vessel wall enhancement compared with untreated HFD-fed ApoE-/- mice. Mass spectroscopy showed a lower gadolinium concentration in the brachiocephalic artery of treated (minocycline = 28.5 ± 3 μmol/L, ebselen = 32.4 ± 4 μmol/L) compared with untreated HFD-fed ApoE-/- mice (191 ± 4.8 μmol/L) (P < 0.02). Both interventions resulted in a lower plaque burden as measured by delayed-enhancement MRI (minocycline = 0.14 ± 0.02 mm2, ebselen= 0.20 ± 0.09 mm2), untreated = 0.44 ± 0.01 mm2; P < 0.001) and histology (minocycline = 0.13 ± 0.05 mm2, ebselen = 0.18 ± 0.02 mm2, untreated = 0.32 ± 0.04 mm2; P < 0.002). Endothelium cells displayed fewer structural changes and smaller gap junction width in treated compared with untreated animals as seen by electron microscopy (minocycline=42.3 ± 8.4 nm, ebselen = 56.5 ± 17 nm, untreated = 2400 ± 39 nm; P < 0.001). Tissue flow cytometry of the brachiocephalic artery showed lower monocyte/macrophage content in both ebselen- and minocycline-treated mice (8.06 ± 3.2% and 7.62 ± 1.73%, respectively) compared with untreated animals (20.1 ± 2.2%) (P = 0.03), with significant attenuation of the proinflammatory Ly6Chigh subtype (untreated mice, 42.64 ± 6.1% of total monocytes; ebselen, 14.07 ± 9.5% of total monocytes; minocycline, 26.42 ± 0.6% of total monocytes).. We demonstrate that contrast-enhanced MRI with an albumin-binding contrast agent can be used to noninvasively monitor the effect of interventions on endothelial permeability and plaque burden. Blood albumin leakage could be a surrogate marker for the in vivo evaluation of interventions that aim at restoring endothelial integrity.

Topics: Albumins; Animals; Anti-Bacterial Agents; Antioxidants; Atherosclerosis; Azoles; Contrast Media; Endothelium, Vascular; Gadolinium; Isoindoles; Magnetic Resonance Imaging; Male; Mice; Minocycline; Organometallic Compounds; Organoselenium Compounds; Permeability

This study examined the protective effect of ischemic postconditioning (IPoC) and minocycline postconditioning (MT) on myocardial ischemia-reperfusion (I/R) injury in atherosclerosis (AS) animals and the possible mechanism. Forty male healthy rabbits were injected with bovine serum albumin following feeding on a high fat diet for 6 weeks to establish AS model. AS rabbits were randomly divided into 3 groups: (1) I/R group, the rabbits were subjected to myocardial ischemia for 35 min and then reperfusion for 12 h; (2) IPoC group, the myocardial ischemia lasted for 35 min, and then reperfusion for 20 s and ischemia for 20 s [a total of 3 cycles (R20s/I20s×3)], and then reperfusion was sustained for 12 h; (3) MT group, minocycline was intravenously injected 10 min before reperfusion. The blood lipids, malondialdehyde (MDA), superoxide dismutase (SOD), soluble cell adhesion molecule (sICAM), myeloperoxidase (MPO), and cardiac troponin T (cTnT) were biochemically determined. The myocardial infarction size (IS) and apoptosis index (AI) were measured by pathological examination. The expression of bcl-2 and caspase-3 was detected in the myocardial tissue by using reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the AS models were successfully established. The myocardial IS, the plasma levels of MDA, sICAM, MPO and cTnT, and the enzymatic activity of MPO were significantly decreased, and the plasma SOD activity was significantly increased in IPoC group and MT group as compared with I/R group (P<0.05 for all). The myocardial AI and the caspase-3 mRNA expression were lower and the bcl-2 mRNA expression was higher in IPoC and MT groups than those in I/R group (all P<0.05). It is concluded that the IPoC and MT can effectively reduce the I/R injury in the AS rabbits, and the mechanisms involved anti-oxidation, anti-inflammation, up-regulation of bcl-2 expression and down-regulation of caspase-3 expression. Minocycline can be used as an effective pharmacologic postconditioning drug to protect myocardia from I/R injury.

Topics: Animals; Atherosclerosis; Ischemic Preconditioning, Myocardial; Male; Minocycline; Myocardial Reperfusion Injury; Rabbits; Reperfusion Injury

Minocycline, a tetracycline derivate, mediates vasculoprotective effects independent of its antimicrobial properties. Thus, minocycline protects against diabetic nephropathy and reduces neointima formation following vascular injury through inhibition of apoptosis or migration, respectively. Whether minocycline has an effect on primary atherogenesis remains unknown.. Using morphological and immunohistochemical analyses we determined de novo atherogenesis in ApoE-/- mice receiving a high fat diet (HFD) with or without minocycline treatment. The effect of minocycline on proliferation, expression of p27(Kip1) or PARP-1 (Poly [ADP-ribose] polymerase 1), or on PAR (poly ADP-ribosylation) modification in vascular smooth muscle cells (VSMC) was analyzed in ex vivo and in vitro (primary human and mouse VSMC).. Minocycline reduced plaque size and stenosis in ApoE-/- HFD mice. This was associated with a lower number and less proliferation of VSMC, reduced PAR (poly ADP-ribosylation) modification and increased p27(Kip1) expression within the plaques. In agreement with the ex vivo data minocycline reduced proliferation, PARP-1 expression, PAR modification while inducing p27 expression in human and mouse VSMC in vitro. These effects were observed at a low minocycline concentration (10 μM), which had no effect on VSMC migration or apoptosis. Minocycline inhibited PARP-1 and induced p27(Kip1) expression in VSMC as efficiently as the specific PARP-1 inhibitor PJ 34. Knock down of p27(Kip1) abolished the antiproliferative effect of minocycline. These data establish a novel antiatherosclerotic mechanism of minocycline during de novo atherogenesis, which depends on p27(Kip1) mediated inhibition of VSMC proliferation.

Topics: Animals; Aortic Valve Stenosis; Apolipoproteins E; Atherosclerosis; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Diet, High-Fat; Humans; Mice; Minocycline; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenanthrenes; Plaque, Atherosclerotic; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

Technetium-99m-labeled matrix metalloproteinase inhibitor (MPI) was used for the noninvasive assessment of matrix metalloproteinase (MMP) activity in atherosclerotic plaques after minocycline (MC) intervention.. MMP activity in atherosclerosis contributes to plaque instability. Some antimicrobial agents may attenuate MMP activity.. Atherosclerotic lesions were produced in 38 rabbits with a high cholesterol diet for 4 months; 5 groups of rabbits, in the fourth month, received fluvastatin (FS) (n = 6), low-dose MC (n = 7), high-dose MC (n = 7), a combination of low-dose MC and FS (n = 6), or no intervention (n = 12); 8 unmanipulated rabbits were used as disease controls. Micro-single-photon emission computed tomography imaging was performed in all animals after intravenous MPI administration, followed by pathologic characterization of the aorta. A cell culture study evaluated the effect of MC on MMP production by activated human monocytes.. MPI uptake was visualized best in untreated atherosclerotic animals (percent injected dose per gram MPI uptake, 0.11 +/- 0.04%). MPI uptake was reduced in the FS (0.06 +/- 0.01%; p < 0.0001), high-dose MC (0.05 +/- 0.01%; p < 0.0001), and MC-FS (0.05 +/- 0.005%; p < 0.0001) groups. Low-dose MC did not resolve MPI uptake significantly (0.08 +/- 0.02; p = 0.167). There was no incremental benefit of the combination of MC and FS. MPI uptake showed a significant correlation with plaque MMP-2, and MMP-9 activity. MMP-9 release from tumor necrosis factor-alpha-activated macrophages was abrogated by incubation with MC.. Molecular imaging of MMP activity in atherosclerotic plaque allows for the study of the efficacy of therapeutic interventions. MC administration resulted in substantial reduction in plaque MMP activity and histologically verified plaque stabilization. MC was found to be equally effective as FS.

Topics: Animals; Anti-Infective Agents; Atherosclerosis; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Metalloproteases; Minocycline; Rabbits

Topics: Aged; Anti-Bacterial Agents; Atherosclerosis; Female; Femoral Artery; Humans; Minocycline; Necrosis; Pigmentation; Pigmentation Disorders; Skin Pigmentation; Tibial Arteries; Toes