Abstract
Adenine nucleotide translocase 1 (ANT1) transfers ATP and ADP over the mitochondrial inner membrane and thus supplies the cell with energy. This study analyzed the role of ANT1 in the immune response of ischemic heart tissue. Ischemic ANT1 overexpressing hearts experienced a shift toward an anti-inflammatory immune response. The shift was characterized by low interleukin (IL)-1β expression and M1 macrophage infiltration, whereas M2 macrophage infiltration and levels of IL-10, IL-4, and transforming growth factor (TGFβ) were increased. The modulated immune response correlated with high mitochondrial integrity, reduced oxidative stress, low left ventricular end-diastolic heart pressure, and a high survival rate. Isolated ANT1-transgenic (ANT1-TG) cardiomyocytes expressed low levels of pro-inflammatory cytokines such as IL-1α, tumor necrosis factor α, and TGFβ. However, they showed increased expression and cellular release of anti-inflammatory immunomodulators such as vascular endothelial growth factor. The secretome from ANT1-TG cardiomyocytes initiated stress resistance when applied to ischemic wild-type cardiomyocytes and endothelial cells. It additionally prevented macrophages from expressing pro-inflammatory cytokines. Additionally, ANT1 expression correlated with genes that are related to cytokine and growth factor pathways in hearts of patients with ischemic cardiomyopathy. In conclusion, ANT1-TG cardiomyocytes secrete soluble factors that influence ischemic cardiac cells and initiate an anti-inflammatory immune response in ischemic hearts.
Highlights
IntroductionIschemic heart disease is a leading cause of death worldwide [1]
Previous studies have demonstrated that infarcted hearts reduced Adenine nucleotide translocase 1 (ANT1) expression [15]; transgenic Adenine nucleotide translocase (ANT) overexpression compensated for decreased ANT1 protein and attenuated cardiac damage
Mitochondrial function is linked to cytokine expression
Summary
Ischemic heart disease is a leading cause of death worldwide [1]. A better understanding of the regulatory processes in infarcted hearts is crucial in response to ischemic stress. Myocardial intercellular crosstalk coordinates the tissue response in concert with the immune system. The inflammatory response to acute myocardial infarction (MI). Is critical for determining the infarct size and left ventricular remodeling. Inflammation is a significant process involved in disease progression. In the infarct zone, dying cardiac cells release signaling molecules, such as cytokines, chemokines, heat shock proteins, and reactive oxygen species, which trigger the immune response. Macrophages are the first most numerous immune cells that infiltrate the infarcted myocardium [2]
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