Effect of lysophosphatidic acid on the immune inflammatory response and the connexin 43 protein in myocardial infarction

Abstract

Abstract. Lysophosphatidic acid (LPA) is an intermediate product of membrane phospholipid metabolism. Recently, LPA has gained attention for its involvement in the pathological processes of certain cardiovascular diseases. The aim of the present study was to clarify the association between the effect of LPA and the immune inflammatory response, and to investigate the effects of LPA on the protein expression levels of connexin 43 during myocardial infarction. Surface electrocardiograms of myocardial infarction rats and isolated rat heart tissue samples were obtained in order to determine the effect of LPA on the incidence of arrhythmia in rats that exhibited changes in immune status. The results demonstrated that the incidence of arrhythmia decreased when the rat immune systems were suppressed, and the incidence of arrhythmia increased when the rat immune systems were enhanced. The concentration levels of tumor necrosis factor (TNF)-α were determined by ELISA, and the results demonstrated that LPA induced T lymphocyte synthesis and TNF-α release. Using a patch-clamp technique, LPA was shown to increase the current amplitude of the voltage-dependent potassium channels (K v ) and calcium-activated potassium channels (K Ca ) in Jurkat T cells. The protein expression of connexin 43 (Cx43) was determined by immunohistochemical staining. The results indicated that LPA caused the degradation of Cx43 and decreased the expression of Cx43. This effect was associated with the immune status of the rats. There was a further decrease in Cx43 expression in the rats of the immune-enhanced group. To the best of our knowledge, these results provide the first evidence that LPA causes arrhythmia through the regulation of immune inflammatory cells and the decrease of Cx43 protein expression. The present study provided an experimental basis for the treatment of arrhythmia and may guide clinical care. IntroductionAcute myocardial infarction (AMI) is a disease that severely affects the health and life quality of patients. Arrhythmia is a complication of myocardial infarction, which is one of the most severe cardiovascular diseases, and it is the predominant cause of myocardial infarction-associated mortality (1). Since patients with ischemic heart disease are particularly prone to arrhythmias, they are often admitted for arrhythmia monitoring (2). Lysophosphatidic acid (LPA), which is an intermediate product of membrane phospholipid metabolism, is a lipid mediator with various biological functions that are predominantly mediated by specific G protein-coupled receptors (3). As a water-soluble glycerol phospholipid with a simple structure, LPA is secreted from numerous cell types, including platelets, fibroblasts and ovarian cancer cells (4). The concentration of LPA in regional myocardial tissue and plasma increases during myocardial infarction, and it can also cause arrhythmia (5).During myocardial infarction, both the infarcted area and the non-infarcted area exhibit perivasculitis, and the infiltration of a large number of inflammator...

Lysophosphatidic Acid Is Associated With Cardiac Dysfunction and Hypertrophy by Suppressing Autophagy via the LPA3/AKT/mTOR Pathway

“…In addition, LPA can mediate diverse actions on cardiac muscle, including modulation of left ventricular systolic and diastolic pressures ( Xu et al, 2002 ), myocardial contractility ( Cremers et al, 2003 ) and electrophysiological instability ( Wei et al, 2012 ). LPA also enhances ventricular arrhythmias in rabbit heart 2 weeks after a MI ( Zhang et al, 2016 ). Therefore, this report did not exclude the possibility that LPA contributes to cardiac dysfunction by other mechanisms, such as regulation of ventricular arrhythmias ( Zhang et al, 2016 ).…”

“…LPA also enhances ventricular arrhythmias in rabbit heart 2 weeks after a MI ( Zhang et al, 2016 ). Therefore, this report did not exclude the possibility that LPA contributes to cardiac dysfunction by other mechanisms, such as regulation of ventricular arrhythmias ( Zhang et al, 2016 ). LPA infusion increased LPA concentrations in plasma at 5 weeks post-MI.…”

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“…Moreover, it should be noted that it is likely that specific types of depression may be more frequently associated with higher or lower levels of microglial activation [ 56 ], and under some circumstances, antidepressant drugs induce an increase, rather than a decrease, in tumour necrosis factor (TNF-α) and interleukin-6 (IL-6) levels [ 162 ]. Given that LPA can induce TNF-α release [ 163 , 164 ] and IL-6 production [ 142 , 164 , 165 ], the modulation of microglia by LPA may be used as antidepressive approach, at least in specific types of depression.…”

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