Peroxisome proliferator-activated receptor ?/? activation inhibits hypertrophy in neonatal rat cardiomyocytes

With the use of fura 2 measurements in multiple and single cells, we examined whether cysteinyl leukotrienes (CysLT) mediate angiotensin II (ANG II)-evoked increases in cytosolic free Ca2+ concentration ([Ca2+]i) in neonatal rat cardiomyocytes. ANG II-evoked CysLT release peaked at 1 min. The angiotensin type 1 (AT1) antagonist losartan, but not the AT2antagonist PD-123319, attenuated the elevations in [Ca2+]i and CysLT levels evoked by ANG II. Vasopressin and endothelin-1 increased [Ca2+]i but not CysLT levels. The 5-lipoxygenase (5-LO) inhibitor AA-861 and the CysLT1-selective antagonist MK-571 reduced the maximal [Ca2+]i responses to ANG II but not to vasopressin and endothelin-1. While MK-571 reduced the responses to leukotriene D4 (LTD4), the dual CysLT antagonist BAY-u9773 completely blocked the [Ca2+]i elevation to both LTD4and LTC4. These data confirm that ANG II-evoked increases, but not vasopressin- and endothelin-1-evoked increases, in [Ca2+]i involve generation of the 5-lipoxygenase metabolite CysLT. The inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] antagonist 2-aminoethoxydiphenyl borate attenuated the [Ca2+]i responses to ANG II and LTD4. Thus AT1 receptor activation by ANG II is linked to CysLT-mediated Ca2+ release from Ins(1,4,5)P3-sensitive intracellular stores to augment direct ANG II-evoked Ca2+ mobilization in rat cardiomyocytes.

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NMDA receptor activation induces mitochondrial dysfunction, oxidative stress and apoptosis in cultured neonatal rat cardiomyocytes

Physiological Research ◽

10.33549/physiolres.931053 ◽

2007 ◽

pp. 559-569

Author(s):

X Gao ◽

X Xu ◽

J Pang ◽

C Zhang ◽

JM Ding ◽

...

Keyword(s):

Nmda Receptor ◽

Caspase 3 ◽

Receptor Activation ◽

Nmda Receptor Antagonist ◽

Neonatal Rat ◽

Dependent Manner ◽

Rat Cardiomyocytes ◽

Peripheral Tissues ◽

Excitatory Neurotransmitter ◽

Neonatal Rat Cardiomyocytes

Glutamate is a well-characterized excitatory neurotransmitter in the central nervous system (CNS). Recently, glutamate receptors (GluRs) were also found in peripheral tissues, including the heart. However, the function of GluRs in peripheral organs remains poorly understood. In the present study, we found that N-methyl-D-aspartate (NMDA) could increase intracellular calcium ([Ca(2+)]i) level in a dose-dependent manner in cultured neonatal rat cardiomyocytes. NMDA at 10(-4) M increased the levels of reactive oxygen species (ROS), cytosolic cytochrome c (cyto c), and 17-kDa caspase-3, but depolarized mitochondrial membrane potential, leading to cardiomyocyte apoptosis. In addition, NMDA treatment induced an increase in bax mRNA but a decrease in bcl-2 mRNA expression in the cardiomyocytes. The above effects of NMDA were blocked by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), and by ROS scavengers glutathione (GSH) and N-acetylcystein (NAC). These results suggest that stimulation of NMDA receptor in the cardiomyocyte may lead to apoptosis via a Ca(2+), ROS, and caspase-3 mediated pathway. These findings suggest that NMDA receptor may play an important role in myocardial pathogenesis.

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Activation ofβ-Adrenoceptors by Dobutamine May Induce a Higher Expression of Peroxisome Proliferator-Activated Receptorsδ(PPARδ) in Neonatal Rat Cardiomyocytes

The Scientific World JOURNAL ◽

10.1100/2012/248320 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Ming-Ting Chou ◽

Shih-Hsiang Lo ◽

Kai-Chun Cheng ◽

Yin-Xiao Li ◽

Li-Jen Chen ◽

...

Keyword(s):

Troponin I ◽

Cardiac Cells ◽

Cardiac Contraction ◽

Neonatal Rat ◽

Peroxisome Proliferator ◽

Emergency Setting ◽

Dependent Manner ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes ◽

Peroxisome Proliferator Activated Receptors

Recent evidence showed the role of peroxisome proliferator-activated receptors (PPARs) in cardiac function. Cardiac contraction induced by various agents is critical in restoring the activity of peroxisome proliferator-activated receptorsδ(PPARδ) in cardiac myopathy. Because dobutamine is an agent widely used to treat heart failure in emergency setting, this study is aimed to investigate the change of PPARδin response to dobutamine. Neonatal rat cardiomyocytes were used to examine the effects of dobutamine on PPARδexpression levels and cardiac troponin I (cTnI) phosphorylation via Western blotting analysis. We show that treatment with dobutamine increased PPARδexpression and cTnI phosphorylation in a time- and dose-dependent manner in neonatal rat cardiomyocytes. These increases were blocked by the antagonist ofβ1-adrenoceptors. Also, the action of dobutamine was related to the increase of calcium ions and diminished by chelating intracellular calcium. Additionally, dobutamine-induced action was reduced by the inhibition of downstream messengers involved in this calcium-related pathway. Moreover, deletion of PPARδusing siRNA generated the reduction of cTnI phosphorylation in cardiomyocytes treated with dobutamine. Thus, we concluded that PPARδis increased by dobutamine in cardiac cells.

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Resistin-Like Molecule α Dysregulates Cardiac Bioenergetics in Neonatal Rat Cardiomyocytes

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.574708 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bingdong Tao ◽

Santosh Kumar ◽

Jose Gomez-Arroyo ◽

Chunling Fan ◽

Ailan Zhang ◽

...

Keyword(s):

Heart Failure ◽

Expression System ◽

Pulmonary Artery Hypertension ◽

Neonatal Rat ◽

Peroxisome Proliferator ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes ◽

Ventricular Afterload ◽

Mitochondrial Fatty Acid ◽

Metabolic Remodeling

Heart (right) failure is the most frequent cause of death in patients with pulmonary arterial hypertension. Although historically, increased right ventricular afterload has been considered the main contributor to right heart failure in such patients, recent evidence has suggested a potential role of load-independent factors. Here, we tested the hypothesis that resistin–like molecule α (RELMα), which has been implicated in the pathogenesis of vascular remodeling in pulmonary artery hypertension, also contributes to cardiac metabolic remodeling, leading to heart failure. Recombinant RELMα (rRELMα) was generated via a Tet-On expression system in the T-REx 293 cell line. Cultured neonatal rat cardiomyocytes were treated with purified rRELMα for 24 h at a dose of 50 nM. Treated cardiomyocytes exhibited decreased mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and transcription factors PPARα and ERRα, which regulate mitochondrial fatty acid metabolism, whereas genes that encode for glycolysis-related proteins were significantly upregulated. Cardiomyocytes treated with rRELMα also exhibited a decreased basal respiration, maximal respiration, spare respiratory capacity, ATP-linked OCR, and increased glycolysis, as assessed with a microplate-based cellular respirometry apparatus. Transmission electron microscopy revealed abnormal mitochondrial ultrastructure in cardiomyocytes treated with rRELMα. Our data indicate that RELMα affects cardiac energy metabolism and mitochondrial structure, biogenesis, and function by downregulating the expression of the PGC-1α/PPARα/ERRα axis.

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Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) Through NF-κB/Brg1 and TGF-ß1 Pathways Attenuates Cardiac Remodeling in Pressure-Overloaded Rat Hearts

Cellular Physiology and Biochemistry ◽

10.1159/000369747 ◽

2015 ◽

Vol 35 (3) ◽

pp. 899-912 ◽

Cited By ~ 30

Author(s):

Han-Ping Qi ◽

Ye Wang ◽

Qian-Hui Zhang ◽

Jing Guo ◽

Lei Li ◽

...

Keyword(s):

Abdominal Aorta ◽

Cardiac Remodeling ◽

Cardiac Fibroblasts ◽

Neonatal Rat ◽

Cardiomyocyte Hypertrophy ◽

Peroxisome Proliferator ◽

Ang Ii ◽

Peroxisome Proliferator Activated Receptor ◽

Rat Cardiomyocytes ◽

Collagen Iii

Background/Aims: Cardiac remodeling is a common pathophysiological change along with chronic hypertension and myocardial infarction. Recent evidence indicated that cardiac tissue expressed peroxisome proliferator-activated receptor γ (PPARγ). However, the functional role of PPARγ in cardiac remodeling remained unclear. The present study was designed to investigate the relationship between PPARγ activation and pressure overload-induced cardiac remodeling. Methods: Cardiac remodeling model was successfully established by abdominal aorta ligation. Cardiac fibrosis and cardiomyocyte hypertrophy were simulated by 100 nM angiotensin II (Ang II) in vitro. Haemodynamic parameters, the expressions of Brg1, a-MHC, ß-MHC, transforming growth factor beta 1 (TGF-ß1), collagen-I, collagen-III and NF-γB were examined. Results: Morphological and haemodynamic measurements showed that the activation of PPARγ improved the impaired cardiac function and decreased interstitial fibrosis in cardiac remodeling rats. Further results also showed that the activation of PPARγ inhibited the expressions of Brg1 and TGF-ß1 in the cardiac remodeling hearts. The activation of PPARγ also inhibited the proliferation and collagen production of cardiac fibroblasts, and down-regulated the activity of Brg1 and the expression of TGF-ß1 induced by Ang II in cultured neonatal rat cardiomyocytes and cardiac fibroblasts, respectively, through NF-γB pathway. Conclusions: These results suggested that PPARγ activation effectively inhibited cardiac remodeling processes by suppression of Brg1 and TGF-ß1 expressions through NF-γB pathway in the pressure-overloaded hearts induced by abdominal aorta ligation in rats.

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