INTRODUCTION:
Coronary heart disease (CHD) (also known as coronary artery disease or ischemic heart disease) is the most common form of heart disease and results from atherosclerosis, or the accumulation of fatty plaques in artery walls that cause narrowing of the artery lumen 1. Menopause is a risk factor for Coronary heart disease because esterogen withdrawal detrimental effect on cardiovascular function and metabolism the menopause compounds many cardiovascular disease risk factors including changes in body fat distribution, reduced glucose tolerance, abnormal plasma lipids, increased blood pressure, endothelial dysfunction, and vascular inflammation 2,3,4,5.
Estradiol (E2) is known to relax arteries directly via endothelial NO and thus exert potential anti-atherogenic effects 6. Also, estradiol prevents early atheroma through endothelial-mediated mechanisms 7. Estrogen exerts its anti-inflammatory effects on the vasculature through different mechanisms such as direct antioxidant effect, generation of nitric oxide, prevention of apoptosis in vascular cells and suppression of cytokines and the renin-angiotensin system 8,9.
Cyclophilin A (CYP-A) is an inflammatory mediator in atherogenesis, the mechanistic role of cyclophilin A in vascular disease progression 10. Cyclophilin A has been shown to elicit inflammatory responses and thus contribute to recruitment of circulating blood cells during inflammatory response 11. Previous Study with mutant CYP-A proteins show that CYP-A can induce chemotaxis and signaling via two distinct pathways: (i) extracellular binding to CD147 12and (ii) PPiase activity13.
MATERIALS AND METHODS:
Patients and healthy groups
Seventy patients were divided into three study groups : acute myocardial infarction patients group included 23 subjects, unstable angina patients group included 22 subjects and stable angina patients group included 25 subjects, the control group was composed of twenty healthy women . The samples were collected from the coronary care unit (CCU) in Al-Sadder Teaching City in Al Najaf province/ Iraq, during the period from January till April,2016 .The ages of patients and control were ranging from 40 to 69 years old.
Collection of blood samples
Five milliliters of venous blood samples were drown using a disposable needle and plastic syringes from each patients and controls subject. Blood was left at room temperature for 10 minutes to clot, centrifuged 6000 rpm for 10 minutes, and then serum was separated and transported into new disposable tubes.
BIOCHEMICAL MARKERS:
Determination of serum Estradiol level
Specific kit for measurement human estradiol concentrations in serum was supplied by (AccuBind™., Monobind Inc. USA-Catalog No. 4925-300).
Determination of serum Cyclophilin-A level
Specific kit for measurement human CYP-A concentrations in serum was supplied by Elabscience Biotechnology Co., Ltd. A Catalog No: E-EL-H1934.
Statistical Analysis:
The data of present study were articulated as (Mean± Standard Error), the statistical analysis (descriptive statistics, Correlation coefficients, p value) were calculated by using megastat and Graphpad prism, when P value<0.05 was statistically a significant 14.
RESULTS:
Comparison of lipid profile between coronary heart disease CHD and healthy group in menopausal women.
The result in table (1) exhibit significant decrease (p<0.05) in serum level of E2 (4.338±0.147pg/ml) in CHD group compared with (11.449±0.271pg/ml) in HT group, while the results in the same table exhibit significant increase (p<0.05) in serum level of CYP-A (13.763± 0.465ng/ml) in CHD group compared with (7.621±0.328ng/ml) in HT group.
Table (1): Comparison of Serum level lipid profile between CHD and HT group in menopausal women.
|
|
Mean ±S.E. |
|
|
HT |
CHD |
|
|
E2 |
11.449±0.271pg/ml |
4.338±0.147pg/ml* |
|
CYP-A |
7.621±0.328ng/ml |
13.763± 0.465ng/ml* |
(*) :represent the significant differences at (p<0.05).
Comparison of lipid profile between Stable-angina (SA), Unstable-angina (UA) and Acute myocardial-infarction (AMI) of CHD menopausal women.
The result in table (2) exhibit a significant decrease (p<0.05) in serum of E2 (3.136±0.212pg/ml) in AMI group and (4.290±0.158pg/ml) in UA group compared with (5.589±0.172pg/ml) in SA group of CHD.
While the results in the same table showed there is a significant increase (p>0.05) of serum CYP-A concentration in AMI group (17.080±0.681ng/ml) as compare with UA group (14.194±0.717ng/ml) and SA group (10.015±0.634ng/ml) of CHD.
Table (2): Comparison of Serum level lipid profile between SA, UA and AMI of CHD menopausal women.
|
|
Mean ±S.E. |
||
|
SA |
UA |
AMI |
|
|
E2 |
5.589± 0.172pg/ml a |
4.290± 0.158pg/ml b |
3.136± 0.212pg/ml c |
|
CYP-A |
10.015± 0.634ng/ml a |
14.194± 0.717ng/ml b |
17.080± 0.681ng/ml c |
The different letters (a, b, c):represent the significant differences at (p<0.05).
The correlation estradiol with cyclophilin-A
The figure(1) indicated, there is a significant negative association (P<0.05, r = - 0.878) between CYP-A and estradiol concentrations of CHD in menopausal women.
Figure (1): Correlation between serum estradiol and serum cyclophilin-A levels of CHD in menopausal women.
DISCUSSION:
The present study indicate a significant decrease (p>0.05)in serum level estradiol in CHD of menopausal decease in comparison of healthy group. The incidence of cardiovascular disease and hyperlipidemia increases with age in both the sexes, but in women the risk increases markedly after menopause 15. The average age of menopause is 50.5 yrs, but some women may enter menopause at earlier age. After menopause, as there is loss of ovarian functions and depletion of various ovarian hormones, these results in adverse changes in glucose and insulin metabolism, body fat distribution, lipid metabolism, coagulation, fibrinolysis and vascular endothelial dysfunction, because of the aging and menopausal effects, the women will enhance total body fatmass, favoring the central body fat dissemination. Age, menopause and central obesity were all independent and important factors to the cardiovascular disease risk factors in women 16,17,18.
The incidence of coronary heart disease in menopausal women correlated with decrease in estrogen level that may be effected of increased of vascular and platelet nitric oxide production since reduce vascular tone, platelet aggregation and vascular growth may explain why menopausal women have high prevalence of hypertension and atherosclerosis19.An assortment of factors can add to endothelial dysfunction, hypertension elevates the shear forces that cause chronic intimal injury which lead to the coronary endothelium mainly close bifurcations, that intimal injury permit for the lipid accumulation, macrophages and the source of the intimal plaque (LDL) which are the source of most lipids in atherosclerotic plaques 20.
The rupture in the plaque can create thrombosis and a complicated injury. This acute thrombus can make complete or incomplete occlusion that additionally diminishes blood stream to the myocardium when combined with vasospasm21. Microvascular disease or endothelial dysfunction or both perhaps add to diminished blood stream to the myocardium. The period and sternness of blood stream diminution determines the sternness of coronary disorder signs: (unstable angina) or myocardial infarction 22.
The present study indicated a significant elevate(p<0.05) in serum cyclophilin-A concentration in coronary heart disease of menopausal women in comparison of healthy group. The study of Jinet al. 23 demonstrated that CYP-A activates endothelial cell in a way that would induce atherogenesis. These study proposed that reactive oxygen species created locally (like via vascular smooth muscle cells and monocytes) makes vascular smooth muscle cells and probably endothelial cell to release CYP-A, the released CYP-A now connects to endothelial cell and induces inflammation and apoptosis, These progressions result in employment of extra inflammatory cells and atherosclerosis progression through a positive feedback system. The reactive oxygen species represent a common pathogenic mechanism for atherosclerosis 24,25. A mainly essential mechanism for ROS mediated CVD appears to be as a result of induction of proinflammatory phases 26,27.
The CYP-A is released from endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, activated macrophages and platelets by a greatly regulated pathway that involves vesicle transfer and plasma membrane binding28. Many vascular cells components release CYP-A by a method which requires reactive oxygen species creation, RhoA/Rhokinase activation and vesicleformation29. In endothelial cells, extracellular CYP-A elevates pro inflammatory pathways including enhanced releasing of adhesion molecules and stimulates atherosclerosis30. In vascular smooth muscle, extracellular CYP-A induces Janus protein tyrosinekinase, ERK1/2 and Akt, and that contribute to reactive oxygen species creation31. In inflammatory cells, extracellular CYP-A works like a chemo-attractant in assistance with other chemokines and cytokines, theCD147 was acts as an extracellular receptor in support of CYP-A in inflammatory cells32,33.
The study of Satoh et al. 34 indicated that the CYP-A are notably elevated in patients with angiographically- who confirmed have Coronary arterial disease, notably, CYP-A concentrations were raised in patients with dyslipidemia, diabetes, hypertension, advanced age and smoking, every one of that are atherosclerotic risk factors in addition to that are reactive oxygen species-inducers ,also these investigation revealed a highly CYP-A expression in the coronary arteries of patients with acute myocardial infarction, this expression was restricted to the district just underneath the thin fibrous cap of the atherosclerotic plaque, and CYP-A may perhaps play an important role in numerous phases of atherosclerosis.
The study of Seizer et al.35 indicated that CYP-A is applies an assortment of functions because of its peptidyl prolylcistrans isomerase (PPIase) action, when discharged in to the extracellular space, CYP-A links to its extracellular receptorCD147 and along these lines starts a cascade of inflammatory processes, that investigation demonstrate that both intra- and extra-cellular CYP-A notably contribute to cardiovascular inflammation, acute myocardial ischemia and reperfusion damage, and myocardial remodeling processes. therefore, CYP-A seems to stand for a novel target to treat vascular and myocardial inflammation.
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Received on 19.03.2017 Modified on 25.03.2017
Accepted on 05.05.2017 © RJPT All right reserved
Research J. Pharm. and Tech. 2017; 10(6): 1675-1678.
DOI: 10.5958/0974-360X.2017.00295.5