Short communication

Effect of cigarette smoking on plasma metalloproteinase-9 concentration

Accumulating evidence suggests that the detrimental effect of nicotine and tobacco smoke on the central nervous system (CNS) is caused by the neurotoxic role of nicotine on blood-brain barrier (BBB) permeability, nicotinic acetylcholine receptor expression, and the dopaminergic system. The ultimate consequence of these nicotine associated neurotoxicities can lead to cerebrovascular dysfunction, altered behavioral outcomes (hyperactivity and cognitive dysfunction) as well as future drug abuse and addiction. The severity of these detrimental effects can be associated with several biological determinants. Sex and age are two important biological determinants which can affect the pharmacokinetics and pharmacodynamics of several systemically available substances, including nicotine. With regard to sex, the availability of gonadal hormone is impacted by the pregnancy status and menstrual cycle resulting in altered metabolism rate of nicotine. Additionally, the observed lower smoking cessation rate in females compared to males is a consequence of differential effects of sex on pharmacokinetics and pharmacodynamics of nicotine. Similarly, age-dependent alterations in the pharmacokinetics and pharmacodynamics of nicotine have also been observed. One such example is related to severe vulnerability of adolescence towards addiction and long-term behavioral changes which may continue through adulthood. Considering the possible neurotoxic effects of nicotine on the central nervous system and the deterministic role of sex as well as age on these neurotoxic effects of smoking, it has become important to consider sex and age to study nicotine induced neurotoxicity and development of treatment strategies for combating possible harmful effects of nicotine. In the future, understanding the role of sex and age on the neurotoxic actions of nicotine can facilitate the individualization and optimization of treatment(s) to mitigate nicotine induced neurotoxicity as well as smoking cessation therapy. Unfortunately, however, no such comprehensive study is available which has considered both the sex- and age-dependent neurotoxicity of nicotine, as of today. Hence, the overreaching goal of this review article is to analyze and summarize the impact of sex and age on pharmacokinetics and pharmacodynamics of nicotine and possible neurotoxic consequences associated with nicotine in order to emphasize the importance of including these biological factors for such studies.

Matrix metalloproteinases (MMP) are a family of zinc-containing endoproteinases that degrade extracellular matrix (ECM) components. MMP have important roles in the development, physiology and pathology of cardiovascular system. Metalloproteases also play key roles in adverse cardiovascular remodeling, atherosclerotic plaque formation and plaque instability, vascular smooth muscle cell (SMC) migration and restenosis that lead to coronary artery disease (CAD), and progressive heart failure. The study of MMP in developing animal model cardiovascular systems has been helpful in deciphering numerous pathologic conditions in humans. Increased peripheral blood MMP-2 and MMP-9 in acute coronary syndrome (ACS) may be useful as noninvasive tests for detection of plaque vulnerability. MMP function can be modulated by certain pharmacological drugs that can be exploited for treatment of ACS. CAD is a polygenic disease and hundreds of genes contribute toward its predisposition. A large number of sequence variations in MMP genes have been identified. Case-control association studies have highlighted their potential association with CAD and its clinical manifestations. Although results thus far are inconsistent, meta-analysis has demonstrated that MMP-3 Glu45Lys and MMP-9 1562C/T gene polymorphisms were associated with CAD risk.

Thiazolidinediones have anti-atherothrombotic effects in diabetic patients. However, the effects of rosiglitazone on inflammatory and hemostatic markers, as well as global endothelial function in non-diabetic smokers are unknown.

Twenty-seven healthy male heavy smokers without metabolic syndrome were enrolled in this double-blind, controlled study. Fourteen subjects received 4 mg/day rosiglitazone for 8 weeks (group R) and 13 subjects received placebo (group C). Changes in the reflection index (ΔRI) of β-agonist-induced endothelium-dependent vasodilatation by photoplethysmography and plasma biomarkers were measured before and after treatment.

Matrix metalloproteinase-9, fibrinogen, and high-sensitivity C-reactive protein were reduced significantly in group R after treatment as compared with the baseline [84.1 (45.6 139.0) vs. 123.9 (58.4 141.8) ng/mL, p = 0.03; 2914 (2400-3553) vs. 3220 (2542-3940) mg/L, p = 0.04; and 3.4 (2.2 5.1) vs. 5.5 (4.1 6.8) mg/L, p = 0.009, respectively]. ΔRI was improved markedly in group R as compared with the baseline [13.5 (4.2 65.1) vs. 2.5 (−10.6 to 9.3)%; p = 0.024]. These biomarkers and ΔRI did not differ significantly in the group C. There were no significant changes in fasting plasma glucose, insulin, homeostasis model assessment index, and lipid profile in both groups R and group C.

Rosiglitazone significantly reduces plasma levels of inflammatory and hemostatic biomarkers, and restores global endothelial dysfunction, independently from insulin sensitization, in healthy smokers.

El tabaquismo es un importante factor de riesgo cardiovascular cuyo mecanismo no se ha definido con precisión, aunque se ha propuesto que las alteraciones del balance entre síntesis y degradación de la matriz extracelular (MEC) pueden ser relevantes. El objetivo de este estudio es examinar si existe una asociación independiente entre el tabaquismo y la concentración circulante de metaloproteinasas (MMP) en sujetos sin síntomas cardiovasculares.

Se ha analizado el perfil metabólico, el espesor íntima-media carotídeo (EIMc), marcadores inflamatorios (fibrinógeno, proteína C reactiva, interleucina 6) y de daño endotelial (factor de von Willebrand), así como la concentración de MMP (1, 9 y 10) y su inhibidor (TIMP-1), en 400 sujetos asintomáticos con factores de riesgo cardiovascular, divididos en no fumadores (n = 195), fumadores (n = 118) y ex fumadores (n = 87). Asimismo se determinó el riesgo vascular total (PROCAM y REGICOR).

El grupo de fumadores presentaba un aumento significativo de MMP-1 (p < 0,05) y MMP-10 (p < 0,001) respecto a los no fumadores, sin diferencias en MMP-9, TIMP-1, EIMc u otros parámetros inflamatorios. Las concentraciones de MMP-10 se correlacionaron con los índices PROCAM y REGICOR (p < 0,001). La asociación entre tabaquismo y MMP-10 se mantuvo en el análisis multivariable tras ajustar por edad, sexo y factores de riesgo cardiovascular (p < 0,01). En análisis de regresión múltiple, el tabaquismo contribuyó al 28% de la variabilidad en las cifras de MMP-10.

La MMP-10 se asoció de forma independiente con el tabaquismo en sujetos asintomáticos. La relación entre MMP-10 y MEC podría indicar un papel de esa MMP en el proceso aterosclerótico asociado al tabaquismo.

Smoking is an important cardiovascular risk factor whose underlying mechanism is incompletely understood. However, it has been suggested that alterations in the balance between synthesis and degradation of the extracellular matrix (ECM) may play a role. The aim of this study was to determine whether there is an independent association between smoking and the concentration of circulating metalloproteinases (MMPs) in individuals without cardiovascular disease.

Metabolic parameters, the carotid intimamedia thickness (IMT), inflammatory markers (fibrinogen, C-reactive protein and interleukin-6), markers of endothelial damage (e.g., von Willebrand factor), and the concentration of MMP-1, -9 and -10 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in 400 asymptomatic individuals with cardiovascular risk factors. Subjects were divided into non-smokers (n=195), smokers (n=118) and former smokers (n=87). In addition, global cardiovascular risk was determined from PROCAM and REGICOR scores.

Both MMP-1 and MMP-10 concentrations were significantly higher in smokers than non-smokers (P<.05 and P<.001, respectively), though there was no difference in the levels of MMP-9, TIMP-1, IMT and other inflammatory parameters. There were positive correlations between the MMP-10 concentration and PROCAM and REGICOR scores (P<.001). Multivariate analysis showed that there was still an association between smoking and the MMP-10 concentration after adjustment for age, sex and other cardiovascular risk factors (P<.001). Multiple regression analysis showed that smoking accounted for 28% of the variability in the MMP- 10 concentration.

There was an independent association between smoking and the MMP-10 concentration in asymptomatic individuals. This relationship between MMP-10 and the ECM may indicate a mechanism through which this MMP contributes to smoking-related atherosclerosis.

Las alteraciones en la síntesis y/o la degradación de la matriz extracelular (MEC) emergen como procesos clave en el desarrollo de la aterosclerosis y sus complicaciones trombóticas. Se ha observado una asociación entre los biomarcadores circulantes de la MEC y las manifestaciones clínicas y los factores de riesgo ateroscleróticos. Diversas metaloproteasas (MMP), endopeptidasas que degradan la MEC, como MMP-9 y 10, además de desempeñar un papel relevante en la fisiopatología del proceso aterotrombótico y contribuir a la expansión de los aneurismas arteriales, pueden ser de utilidad como biomarcadores de riesgo aterosclerótico y predictores de recurrencia de enfermedad coronaria y cerebrovascular. Aunque actualmente el papel de los inhibidores de MMP (TIMP) en el pronóstico cardiovascular es más incierto, la MEC puede representar una diana terapéutica atractiva en la aterotrombosis, y diversos inhibidores de las MMP se encuentran en fase de investigación clínica.

Defects in the synthesis and breakdown of the extracellular matrix (ECM) are now seen as key processes in the development of atherosclerosis and its thrombotic complications. Correlations have been observed between circulating levels of ECM biomarkers and the clinical manifestations of and risk factors for atherosclerosis. Several matrix metalloproteinases (MMPs), endopeptidases that can degrade the ECM, such as MMP-9 and MMP-10, play important roles in the pathophysiology of atherothrombosis and contribute to the expansion of abdominal aortic aneurysms. Moreover, they may also be useful biomarkers of atherosclerotic risk and serve as predictors of coronary and cerebrovascular disease recurrence. Although at present the effect of tissue inhibitors of MMPs (TIMPs) on cardiovascular disease prognosis is still uncertain, the ECM could be a promising therapeutic target in atherothrombotic disease, and several MMP inhibitors are currently undergoing clinical trials.

This study investigated whether reduced levels of circulating endothelial progenitors cells (EPCs) in chronic heart failure (CHF) are secondary to an exhaustion of hematopoietic stem cells (HSCs) in the bone marrow or to reduced mobilization.

Circulating EPCs presumably originate from bone marrow-derived HSC. Persistent mobilization of EPCs was shown to be associated with favorable left ventricular infarct remodeling processes.

We assessed the number and functional capacity of EPCs in 17 healthy controls, 25 patients with ischemic cardiomyopathy (ICM), and 20 patients with dilated cardiomyopathy (DCM). To document an impairment of HSC function in the bone marrow, the colony-forming unit capacity of bone marrow–derived mononuclear cells and the number of CD34⁺HSCs were examined in 6 healthy volunteers, 94 ICM patients, and 25 DCM patients.

The number of EPCs was reduced in CHF, irrespective of its etiology. In contrast, the migratory capacity was selectively impaired in EPCs of ICM patients (4.8 ± 4.0 migrated cells; DCM 9.7 ± 5.8; p = 0.02). On multivariate analysis, ICM, advanced New York Heart Association functional class, and CHF were independent predictors of functional EPC impairment. The number of bone marrow-derived CD34⁺cells did not differ between the CHF populations. However, colony-forming units (CFUs) were selectively reduced in ICM patients (54.4 ± 24.6; DCM 68.1 ± 26.9; p < 0.02). Ischemic cardiomyopathy was the only independent predictor of impaired CFU capacity. Impaired CFU capacity was associated with reduced matrix metalloproteinase-9 activity in the bone marrow plasma.

Ischemic cardiomyopathy is associated with selective impairment of progenitor cell function in the bone marrow and in the peripheral blood, which may contribute to an unfavorable left ventricular (LV) remodeling process.