Background: Offspring of patients with early myocardial infarction have a higher risk to develop cardiovascular events; the underlying physiopathology is still unclear.
Several lines of evidence support a role for oxidative stress in atherogenesis and NADPH oxidase-2 (NOX-2) is considered a major source of O2- in human. Thus, oxidative stress regulates arachidonic acid metabolism via activation of platelet phospholipase-A2.
Furthermore, recent studies suggested that changes of gut microbiota is associated to cardiovascular disease. In particular, lipopolysaccharide (LPS) derived from Gram-negative bacteria, is believed to play a role in causing atherosclerosis by increase of oxidative stress and inflammation.
The aim of this study is to address NOX-2 activity as well as serum thromboxane B2 (TXB2), 8-isoPGF2-alpha and LPS in offspring of patients with premature myocardial infarction.
Methods: Ninety-two consecutive subjects, including 46 offspring of patients with premature myocardial infarction and 46 healthy subjects (HS) matched for age and gender, will be recruited.
A cross sectional study will be performed to compare serum activity of soluble NOX-2-dp (sNOX-2-dp), blood levels of isoprostanes and serum TXB2 in these two groups; LPS and zonuline levels will be analyzed. Serum zonulin, will be assessed as measure of gut permeability.
Univariate and multivariate analysis will be performed to to define the independent predictors of sNOX-2-dp and serum isoprostanes.
This study want to evaluate if Nox-2 activation is a key determinant of oxidative stress and platelet activation in offspring of patients with premature myocardial infarction and if gut mycrobiota could play a role in this pathogenic process.
This study could provide the first report attesting that offspring of patients with premature myocardial infarction have high NOX-2 activation, serum isoprostanes and TXB2 levels, and could suggest a potential role for oxidative stress in platelet activation in this population at high cardiovascular risk.
NOX-2 is considered a key target in atherosclerosis [14,15] and platelet activation [6]. Reactive oxygen species (ROS) generated by NOX-2 inactivate nitric oxide, an endogenous platelet inhibitor [10]. On the other hand, ROS generated by NOX-2 may interact with arachidonic acid to produce isoprostanes, which are molecules contributing to spread platelet aggregation [16]. Consistent with this, previous studies showed that NOX-2 down-regulation is associated with impaired isoprostanes formation and enhanced NO generation [7,17].
In this study we want to assess if, compared to controls, serum levels of sNOX-2-dp and isoprostanes levels are higher in offspring of patients with premature myocardial infarction. The increased oxidative stress, observed in this high risk cardiovascular population, was described in a previous paper by Kelishadi that found high OX-LDL levels in children with a positive family history of premature CHD [18].
Previous studies showed that NOX-2 generated oxidative stress contributes to isoprostanes formation and to platelet activation [6]. In this study we want to assess if children of patients with precocious myocardial infarction have increased levels of TXB2 as maer of increased platelet activation. A potential implication of these findings could be that down-regulating NOX-2 might be useful to modulate platelet activation and eventually cardiovascular risk but prospective studies (e.g. with statins or antioxidants) are necessary to establish a cause-effect relationship between NOX-2-related oxidative stress and cardiovascular events.
This study could contribute to increase knowledge in this field showing if NOX-2 activation is a key determinant of oxidative stress and platelet activation in offspring of patients with premature myocardial infarction.
References:
[14] L. Loffredo, A.M. Zicari, F. Occasi, L. Perri, R. Carnevale, F. Angelico, et al., Endothelial
dysfunction and oxidative stress in children with sleep disordered breathing: role of
NADPH oxidase, Atherosclerosis. (2015) 222¿227.
[15] L. Loffredo, A.M. Zicari, F. Occasi, L. Perri, R. Carnevale, F. Angelico, et al., Role of NADPH oxidase-2 and oxidative stress in children exposed to passive smoking, Thorax. 73 (2018) 986¿988.
[16] R. Carnevale, L. Loffredo, V. Sanguigni, A. Plebani, P. Rossi, C. Pignata, et al., Different
degrees of NADPH oxidase 2 regulation and in vivo platelet activation: lesson from
chronic granulomatous disease, J. Am. Heart Assoc. 3 (2014), e000920.
[17] F. Violi, P. Pignatelli, C. Pignata, A. Plebani, P. Rossi, V. Sanguigni, et al., Reduced atherosclerotic burden in subjects with genetically determined low oxidative stress,
Arterioscler. Thromb. Vasc. Biol. 33 (2013) 406¿412.
[18] R. Kelishadi, M. Sabri, N.Motamedi,M.A. Ramezani, Factor analysis ofmarkers of inflammation and oxidation and echocardiographic findings in children with a positive family history of premature coronary heart disease, Pediatr. Cardiol. 30 (2009) 477¿481.