MetS is well recognized as an aggregate of cardio-metabolic risk factors subsequent cardiovascular disease and type 2 diabetes mellitus [23, 24], and the association of PEDF with MetS and its components has been verified in previous studies [12–14]. In a 10-year prospective study, enhanced PEDF level was identified as an independent predictor for the development of MetS in men , which further affirmed the prediction effect of PEDF on MetS. However, these studies focused solely on subjects with CAD risk factors but no clinical evidence of cardiovascular disease, which may have limited their ability to extend this relation of serum PEDF with MetS to the subsequent onset of cardiovascular disease. To overcome this limitation, the present study enrolled CAD and non-CAD subjects (~3:4 ratio) as well as MetS and non-MetS subjects (~2:3 ratio) and still found that serum PEDF level was significantly increased in the MetS patient group. This finding agrees with previous functional studies that indicated enhanced levels of PEDF might exert a counteractive activity against simultaneous enhancement of CAD risk factors [13, 14].
In the current study of the broad panel of MetS pathogenic components, PEDF was found to be significantly positively correlated with hypertriglyceridemia, and TG was identified as an independent influencing factor of serum PEDF levels. Dyslipidemia is known to play an important role in the development of atherosclerosis and CAD. Specifically, long-term dyslipidemia has been shown to cause physical injury to the vascular intima, and the accompanying pro-inflammatory state of the tissue promotes atherosclerosis and CAD. In clinical studies, patients with elevated TG levels developed CAD more frequently than their counterparts with TG levels in the normal range and TG has been identified as an independent risk factor for coronary events [25, 26]. In the current study, TG was found to be strongly and independently correlated with serum PEDF in patients with CAD or at high risk of CAD. Moreover, these findings also agree with the previous studies in patients without CAD history [12, 13]. It is possible that the enhanced levels of serum PEDF in CAD or CAD-risk patients reflect a response to hypertriglyceridemia, whereby the body is attempting to correct the perturbance in the lipid metabolism system . Intriguingly, we failed to find any significant association of serum PEDF with the other two principal components of MetS, central obesity and hypertension. These negative findings may be explained by the fact that a large portion of our subjects had been receiving therapeutic treatments for hyperglycemia, hypertension, or hyperlipidemia for long periods prior to study participation; to account for this potential confounding aspect, hypoglycemia therapy was entered the equation in the multiple regression analysis of PEDF levels. Body weight and W in subjects of this study might have changed in response to a long-term influence of medications; therefore, the relation of PEDF with obesity might be masked by other determinants.
Substantial evidence exists to support the hypothesis that PEDF plays a protective role against microangiopathy; moreover, PEDF has been proposed as a potential protective factor against diabetic microvascular complications [28–30]. Yet, few studies to date have investigated the association of PEDF with macroangiopathy, as was done in the current study which demonstrated for the first time that serum PEDF was independently positively correlated with CAD in a Chinese population. This finding contradicts a previous study by Shiga et al., which showed no significant correlation between PEDF and the presence of CAD in a Japanese population ; however, this apparent inconsistency may merely indicate the different inclusion subjects.
Atherosclerosis, which is considered the pathological basis of CAD, is a chronic inflammatory disorder . Previous studies have shown that CRP was positively correlated with PEDF, and suggested that this relation may reflect the body’s attempt to suppress a detrimental inflammatory reaction involving the endothelial cells [14, 33]. In our study, we found no difference in the CRP levels of CAD and non-CAD patients, possibly because the majority of those non-CAD patients actually possessed many of the CAD risk factors and >60% of them were MetS patients. Regardless, the multivariate stepwise regression analysis performed for the study population identified CRP as an independent influencing factor of serum PEDF levels, and this finding agrees with the proposed association of PEDF with chronic inflammation. Furthermore, oxidative stress, which is elevated in patients with metabolic disorder or CAD, could be one of the triggers in the liver (an important source organ of circulating PEDF), as hydrogen peroxide has been shown to induce PEDF expression in human hepatocytes .
Given the fact that PEDF exerts anti-angiogenic, anti-oxidative, anti-thrombotic, and anti-inflammatory properties on vascular tissues, researchers have speculated that PEDF levels might be elevated to counteract generation of a pro-atherosclerotic environment induced by vascular injuries [16, 17]. Ueda et al. reported that PEDF injection suppressed cardiac fibrosis, inhibited tissue remodeling and improved cardiac function in a rat model of acute myocardial infarction and suggested that PEDF may be a novel therapeutic strategy for human acute myocardial infarction . Since PEDF exerts a number of protective effects on vascular and myocardial tissues, elevated serum PEDF levels in CAD patients may also play a counter-regulatory and protective role against vascular damage caused by hypertriglyceridemia, hyperglycemia, and chronic inflammation.
Moreover, Rychli et al. found that PEDF was significantly associated with CAD (for trend, P = 0.037) and correlated with rehospitalization for heart failure (HF) worsening, with a more prominent risk increase association in CAD patients; these previous findings further support our current results. Rychli et al. also suggested that PEDF was associated with chronic deterioration of cardiomyopathy and played a role in the progression of HF by inducing apoptosis of human cardiac myocytes and fibroblasts . We believe that the elevated PEDF observed in CAD patients occurs in response to vascular injuries, chronic inflammation, and oxidative stress, and that its function involves preventing CAD deterioration.
It has been reported that cardiovascular disease was closely regulated through the signaling pathways of the mammalian target of rapamycin (mTOR) which was associated with endothelial cell survival and growth, as well as cardiomyocyte proliferation . Wang et al. confirmed the antiangiogenic property of PEDF and firstly reported that insulin could down-regulate PEDF expression, which at least partly depended on mTOR kinase as the inhibitory effect of insulin on PEDF expression would disappear when added the mTOR inhibitor rapamycin . It is possible that PEDF would offer exciting prospects for the development of new therapies for cardiovascular disease.
Another physiological factor that was correlated with the elevated PEDF levels in our study population was eGFR (independently negatively correlated). This finding is not surprising since renal filtration is known to affect serum PEDF levels, and is in line with findings from previous studies [15, 31].