Oxidative stress plays an important role in burn-induced myocardial injury, but the cellular mechanisms that control reactiveoxygen species (ROS) production and scavengin... More

Oxidative stress plays an important role in burn-induced myocardial injury, but the cellular mechanisms that control reactiveoxygen species (ROS) production and scavenging are not fully understood. This study demonstrated that blockade of Notchsignaling via knockout of the transcription factor RBP-J or a pharmacological inhibitor aggravated postburn myocardial injury,which manifested as deteriorated serum CK, CK-MB, and LDH levels and increased apoptosis in vitro and in vivo. Interruptionof Notch signaling increased intracellular ROS production, and a ROS scavenger reversed the exacerbated myocardial injury afterNotch signaling blockade. These results suggest that Notch signaling deficiency aggravated postburn myocardial injury throughincreased ROS levels. Notch signaling blockade also decreased MnSOD expression in vitro and in vivo. Notably, Notch signalingblockade downregulated p-JAK2 and p-STAT3 expression. Inhibition of JAK2/STAT3 signaling with AG490 markedly decreasedMnSOD expression, increased ROS production, and aggravated myocardial injury. AG490 plus GSI exerted no additional effects.These results demonstrate that Notch signaling protects against burn-induced myocardial injury through JAK2/STAT3 signaling,which activates the expression of MnSOD and leads to decreased ROS levels. Less

Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective m... More

Molecular mechanisms protecting cardiomyocytes from stress-induced death, including tension stress, are essential for cardiac physiology and defects in these protective mechanisms can result in pathological alterations. Bcl2-associated athanogene 3(BAG3) is expressed in cardiomyocytes and is a component of the chaperone-assisted autophagy pathway, essential for homeostasis of mechanically altered cells. BAG3 ablation in mice results in a lethal cardiomyopathy soon after birth and mutations of this gene have been associated with different cardiomyopathies including stress-induced Takotsubo cardiomyopathy (TTC). The pathogenic mechanism leading to TTC has not been defined, but it has been suggested that the heart can be damaged by excessive epinephrine (epi) spillover in the absence of a protective mechanism. The aim of this study was to provide more evidence for a role of BAG3 in the pathogenesis of TTC. Therefore, we sequenced BAG3 gene in 70 TTC patients and in 81 healthy donors with the absence of evaluable cardiovascular disease. Mutations and polymorphisms detected in the BAG3 gene included a frequent nucleotide change g2252c in the BAG3 3′-untranslated region (3′-UTR) of Takotsubo patients (Po0.05), resulting in loss of binding of microRNA-371a-5p (miR-371a-5p) as evidenced by dual-luciferase reporter assays and argonaute RNA-induced silencing complex catalytic component 2/pull-down assays. Moreover, we describe a novel signaling pathway in cardiomyocytes that leads to BAG3 upregulation on exposure to epi through an ERK-dependent upregulation of miR-371a-5p. In conclusion, the presence of a g2252c polymorphism in the BAG3 3′-UTR determines loss of miR-371a-5p binding and results in an altered response to epi, potentially representing a new molecular mechanism that contributes to TTC pathogenesis. Cell Death and Disease (2015) 6, e1948; doi:10.1038/cddis.2015.280; published online 29 October 2015 Less

Background: Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential applicatio... More

Background: Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs) as well as induced cardiac-like progenitors (iCPs) derived from ASCs for the treatment of myocardial infarction. Methods and results: Human bone marrow (BM)-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM-derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. Conclusion: Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. Keywords: adipose stem cells, myocardial infarction, cellular reprogramming, cellular therapy, piggyBac, induced cardiac-like progenitors Less

Reactive oxygen species trigger cardiomyocyte cell death via increased oxidative stress and have been implicated in the pathogenesis of cardiovascular diseases. The preve... More

Reactive oxygen species trigger cardiomyocyte cell death via increased oxidative stress and have been implicated in the pathogenesis of cardiovascular diseases. The prevention of cardiomyocyte apoptosis is a putative therapeutic target in cardioprotection. Polyphenol intake has been associated with reduced incidences of cardiovascular disease and better overall health. Polyphenols like epigallocatechin gallate (EGCG) can reduce apoptosis of cardiomyocytes, resulting in better health outcomes in animal models of cardiac disorders. Here, we analyzed whether the antioxidant N-acetyl cysteine (NAC) or polyphenols EGCG, gallic acid (GA) or methyl gallate (MG) can protect cardiomyocytes from cobalt or H2O2-induced stress. We demonstrate that MG can uphold viability of neonatal rat cardiomyocytes exposed to H2O2 by diminishing intracellular ROS, maintaining mitochondrial membrane potential, augmenting endogenous glutathione, and reducing apoptosis as evidenced by impaired Annexin V/PI staining, prevention of DNA fragmentation, and cleaved caspase-9 accumulation. These findings suggest a therapeutic value for MG in cardioprotection. Less

Congenital heart disease (CHD) is one of the most prevalent developmental anomalies and the leading cause of noninfectious morbidity and mortality in newborns. Despite it... More

Congenital heart disease (CHD) is one of the most prevalent developmental anomalies and the leading cause of noninfectious morbidity and mortality in newborns. Despite its prevalence and clinical significance, the etiology of CHD remains largely unknown. GATA4 is a highly conserved transcription factor that regulates a variety of physiological processes and has been extensively studied, particularly on its role in heart development. With the combination of TBX5 and MEF2C, GATA4 can reprogram postnatal fibroblasts into functional cardiomyocytes directly. In the past decade, a variety of GATA4 mutations were identified and these findings originally came from familial CHD pedigree studies. Given that familial and sporadic CHD cases allegedly share a basic genetic basis, we explore the GATA4 mutations in different types of CHD. In this study, via direct sequencing of the GATA4 coding region and exon-intron boundaries in 384 sporadic Chinese CHD patients, we identified 12 heterozygous non-synonymous mutations, among which 8 mutations were only found in CHD patients when compared with 957 controls. Six of these non-synonymous mutations have not been previously reported. Subsequent functional analyses revealed that the transcriptional activity, subcellular localization and DNA binding affinity of some mutant GATA4 proteins were significantly altered. Our results expand the spectrum of GATA4 mutations linked to cardiac defects. Together with the newly reported mutations, approximately 110 non-synonymous mutations have currently been identified in GATA4. Our future analysis will explore why the evolutionarily conserved GATA4 appears to be hypermutable. Less

The hypoxic conditions induced by reduced blood flow decreases oxygen availability in target tissues. Cellular hypoxia leads to mitochondrial dysfunction, decreased energ... More

The hypoxic conditions induced by reduced blood flow decreases oxygen availability in target tissues. Cellular hypoxia leads to mitochondrial dysfunction, decreased energy production, and increased production of reactive oxygen species. To determine the alteration in expression of mitochondrial genes after hypoxia in cardiomyocytes, we developed a rodent mitochondrial gene chip (RoMitoChip). The chip had 1088 probe sets including 46 probe sets representing 37 mouse mitochondrial DNA transcripts and the remaining probe sets representing mouse nuclear genes contributing to the mitochondrial structure and function. Mouse cardiomyocytes isolated from neonatal C57BL/6 mice that were subjected to hypoxia (1% oxygen) for different time intervals demonstrated a dichotomy in the expression profile of tRNA and mRNA transcripts. We report a total of 483 signature genes that were altered by hypoxia in the cardiac myocytes and related to mitochondrial structure and function. This includes 23 transcripts on mitochondrial DNA. Pathway analysis demonstrated predominant changes in the expression of genes involved in oxidative phosphorylation, glucose and fatty acid metabolism, and apoptosis. The most upregulated genes after 24 h of hypoxia included hypoxia-inducible factor 1, alpha subunit, inducible genes Bnip3, Pdk1, and Aldoc. Whereas Bnip3 is important in the cardiomyocyte death pathway, Pdk1 enzyme is critical in conserving mitochondrial function by diverting metabolic intermediates to glycolysis. This study identifies the participation of two important pathways, cell death and glycolytic, and two key proteins, Bnip3 and Pdk1, playing critical roles in these pathways in cardiomyocytes after severe hypoxia. Less