Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction

Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Circulation (Impact Factor: 14.43). 03/2008; 117(8):1055-64. DOI: 10.1161/CIRCULATIONAHA.107.749234
Source: PubMed


Despite widespread clinical use as a prognostic marker in ischemic heart disorders, the actual pathogenetic role of the short pentraxin, C-reactive protein, has not undergone stringent genetic testing because of evolutionary divergence between mouse and humans. The long pentraxin PTX3 is conserved in evolution, is expressed in the heart under inflammatory conditions, and is a candidate prognostic marker in acute myocardial infarction. It was therefore important to assess whether PTX3 plays a pathogenetic role in acute myocardial infarction.
In a model of acute myocardial infarction caused by coronary artery ligation and reperfusion, tissue mRNA expression and circulating levels of PTX3 increased. The interleukin-1R-MyD88 pathway plays a pivotal role in the induction of PTX3 transcript after ischemia. ptx3-deficient mice showed exacerbated heart damage (33% larger infarcts in null mice; P=0.0047). Increased myocardial damage in ptx3-deficient mice was associated with a greater no-reflow area, increased neutrophil infiltration, decreased number of capillaries, and increased number of apoptotic cardiomyocytes. In addition, ptx3-deficient mice with acute myocardial infarction showed higher circulating levels of interleukin-6 and increased C3 deposition in lesional tissue. The phenotype was reversed by exogenous PTX3.
Thus, PTX3 plays a nonredundant, regulatory, cardioprotective role in acute myocardial infarction in mice. Our results suggest that modulation of the complement cascade contributes to the cardioprotective function of PTX3.

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Available from: Roberto Latini, May 11, 2014
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    • "c o m Please cite this article as: Slusher AL, et al, The impact of obesity on pentraxin 3 and inflammatory milieu to acute aerobic exercise, Metabolism (2014), with metabolic syndrome [12] [13]. These findings clearly implicate that PTX3 deficiency promotes vascular inflammation, atherosclerosis, and heart damage [14] [15]. It has been well established that increased cardiorespiratory fitness provides anti-inflammation and cardioprotection, thereby reducing the risk of CVD [16] [17] [18] [19]. "
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    ABSTRACT: Pentraxin 3 (PTX3) has recently been linked to obesity-associated inflammation, serving as a cardioprotective modulator against cardiovascular disease (CVD). Aerobic exercise has been shown to enhance plasma PTX3 levels; however, the impact of obesity on PTX3 response to exercise remains unknown. Objective. Therefore, this study sought to examine whether obese subjects would have an attenuated plasma PTX3 response compared to normal-weight subjects following acute aerobic exercise. The relationship of plasma PTX3 with pro-inflammatory cytokines (IL-6 and TNF-α) was also examined. Methods. Twenty healthy subjects (10 obese [4 males and 6 females] and 10 normal-weight [4 males, 6 females]) performed 30 min of continuous submaximal aerobic exercise. Results. At baseline, obese subjects exhibited approximately 40% lower plasma PTX3 and a 7-fold greater IL-6 concentration compared to normal-weight subjects. In response to exercise, no difference was observed in PTX3 or IL-6 as indicated by area-under-the-curve “with respect to increase” (AUCi) analyses. Furthermore, PTX3 AUCi was positively correlated with cardiorespiratory fitness levels (VO2max) (r = 0.594, p = 0.006), even after controlling for body mass index. Conclusion. These findings suggest that in addition to obesity-associated complications, low cardiorespiratory fitness levels could impact exercise-induced PTX3 elevations, thereby potentially diminishing PTX3’s effects of anti-inflammation and/or cardioprotection.
    Metabolism 10/2014; 64(2):323-329. DOI:10.1016/j.metabol.2014.10.022 · 3.89 Impact Factor
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    • "In rats, forced expression of PTX3 reduces neointima formation after balloon injury, indicating that this long pentraxin can limit intimal hyperplasia [9]. PTX3-deficient mice with acute MI showed increased myocardial damage, and exogenous PTX3 expression rescued this phenotype, suggesting a cardioprotective function of PTX3 [10]. Furthermore, PTX3 deficiency in mice worsened atherosclerotic lesions and inflammatory profiles [12]. "
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    ABSTRACT: Chronic inflammation closely associates with obesity, metabolic syndrome, diabetes mellitus, and atherosclerosis. Evidence indicates that the immunomodulator pentraxin 3 (PTX3) may serve as a biomarker of these cardiometabolic disorders, but whether PTX3 predicts cardiovascular complications is unknown. We examined the association of plasma PTX3 levels with recurrent coronary events via a prospective, nested, case-control design in the CARE trial. Among 4159 patients who had a prior myocardial infarction 3 to 20 months before enrollment and also had total cholesterol levels <240 mg/dL and LDL cholesterol levels between 115 and 175 mg/dL, we measured plasma PTX3 levels at baseline by high-sensitivity ELISA in 413 cases with recurrent myocardial infarction or coronary death during a 5-year follow-up period, and in 366 sex- and age-matched controls. Cases with recurrent coronary events and controls had similar PTX3 levels, and PTX3 did not predict recurrent coronary events - a finding that contrasts with that of C-reactive protein (CRP) and serum amyloid A (SAA) in this cohort. We then associated PTX3 levels with metabolic disorders. Low plasma PTX3 levels correlated with high body-mass index, waist circumference, and triglycerides; and with low HDL cholesterol. Overall, PTX3 levels correlated inversely with the number of metabolic syndrome components. PTX3 levels also correlated inversely with apoCIII and tissue plasminogen activator, but did not associate with CRP. Although the study further links low PTX3 levels with various features associated with metabolic syndrome, the results do not indicate that PTX3 can predict recurrent coronary events among MI survivors.
    PLoS ONE 04/2014; 9(4):e94073. DOI:10.1371/journal.pone.0094073 · 3.23 Impact Factor
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    • "The association between PTX3 and negative outcome had been originally proposed to involve direct negative effects of PTX3 in cardiac and vascular tissues [7]. Strong emerging evidence however indicates that PTX3 elevation may represent an adaptive, anti-inflammatory response to pre-existing vascular damage [23,24], and this concept is also supported by differential changes of pro-inflammatory short pentraxin CRP and PTX3 in ACS in the current study. More pronounced tissue damage, rather than PTX3 elevation per se, could therefore be directly responsible for negative outcome in ACS patients with highest PTX3. "
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    ABSTRACT: Long pentraxin 3 (PTX3) is a component of the pentraxin superfamily and a potential marker of vascular damage and inflammation, associated with negative outcome in patients with acute coronary syndromes (ACS). Obesity is a risk factor for cardiovascular disease and PTX3 production is reported in abdominal adipose tissue. Low PTX3 is however reported in the obese population, and obesity per se may be associated with less negative ACS outcome. We investigated the potential impact of obesity and high waist circumference (reflecting abdominal fat accumulation) on plasma PTX3 concentration in ACS patients (n = 72, 20 obese) compared to age-, sex- and BMI-matched non-ACS individuals. Both obese and non-obese ACS patients had higher PTX3 than matched non-ACS counterparts, but PTX3 was lower in obese than non-obese individuals in both groups (all P < 0.05). PTX3 was also lower in ACS subjects with high than in those with normal waist circumference (WC). Plasma PTX3 was accordingly associated negatively with BMI and WC, independently of age and plasma creatinine. No associations were observed between PTX3 and plasma insulin, glucose or the short pentraxin and validated inflammation marker C-reactive protein, that was higher in ACS than in non-ACS individuals independently of BMI or WC. Obesity is associated with low circulating PTX3 in ACS. This association is also observed in the presence of abdominal fat accumulation as reflected by elevated waist circumference. Low PTX3 is a novel potential modulator of tissue damage and outcome in obese ACS patients.
    Cardiovascular Diabetology 11/2013; 12(1):167. DOI:10.1186/1475-2840-12-167 · 4.02 Impact Factor
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