N‑terminal truncated peroxisome proliferator‑activated receptor‑γ coactivator‑1α alleviates phenylephrine‑induced mitochondrial dysfunction and decreases lipid droplet accumulation in neonatal rat cardiomyocytes

Background/Aims: Morphological and biochemical maladaptation of cardiomyocytes are associated with mitochondrial dysfunction and dysregulation in hypertrophic conditions. Peroxisome proliferator activated receptor α (PPARα), a drug target for dyslipidemia, is known to be downregulated in cardiomyocytes in response to hypertrophic stimuli. The current study was undertaken to investigate the role of PPARα signaling in mitochondrial remodeling and thereby dysregulation of cardiomyocytes due to hypertrophy in vitro. Methods: Rat cardiomyocytes H9c2 (2-1) and neonatal rat ventricular myocytes (NRVMs) were cultured and treated with α1-adrenergic agonist phenylephrine (PE, 100 µM, 24 hours) in the presence or absence of 10 µM fenofibrate or bezafibrate. Cellular hypertrophy was observed by atomic force microscopy and immunofluorescence with F-actin antibody. mRNA levels of hypertrophic marker genes and other genes were examined by quantitative real time PCR. Structural as well as functional remodeling of the mitochondria were evaluated by immunofluorescence (F-actin and COX-I), live cell imaging microscopy (JC-I, mitotracker), mitochondrial complex V activity, MPTP activity and ATP assay. Oxidative stress was measured by using sensitive fluorescent indicator probes. Cellular and mitochondrial calcium were measured by using fluorescent indicator probes Rhod-2 AM and X-rhod-1 AM, respectively. Targetscan prediction analysis was performed to find out miRNAs as putative regulators of VDAC. Luciferase assay was conducted to confirm binding of miR28 with VDAC. Results: Co-treatment of H9c2(2-1) cells with PE and fenofibrate restricted increase in cell size and expression of marker genes such as atrial-natriuretic peptide (ANP), brain-natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) compared to those with PE alone. Fenofibrate prevented PE-induced down regulation of PPARα-target genes like CPT-I and MCAD. Mitochondrial trans-membrane potential (Δψm) and motility were reduced by PE which were significantly checked by fenofibrate. Increased ROS production and calcium level in PE-treated cells were ameliorated by fenofibrate. Mitochondrial activity and ATP generation were reduced by PE which was rescued by fenofibrate. Fenofibrate also prevented PE-induced down regulation of mitochondrial genes like VDAC-I and COX-IV. Expression of several miRNAs was altered in hypertrophic cardiomyocytes which were restored when co-treated with fenofibrate. miR28 was found to target 3’ untranslated region of VDAC-I. Conclusion: Overall, the results demonstrate that PPARα signaling is critically involved in mitochondrial dysfunction in hypertrophic cardiomyocytes in which miR28 plays a pivotal role.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

P1738 Involvement of phosphorylation in hypoxia-induced heme oxygenase-1 expression in neonatal rat cardiomyocytes

European Heart Journal ◽

10.1016/s0195-668x(03)94876-7 ◽

2003 ◽

Vol 24 (5) ◽

pp. 331

Author(s):

G WU

Keyword(s):

Heme Oxygenase ◽

Neonatal Rat ◽

Heme Oxygenase 1 ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes

Download Full-text

The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22020934 ◽

2021 ◽

Vol 22 (2) ◽

pp. 934

Author(s):

Woon-Man Kung ◽

Muh-Shi Lin

Keyword(s):

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Management Strategies ◽

Nuclear Factor Κb ◽

Peroxisome Proliferator ◽

Proinflammatory Response ◽

Pharmacological Management ◽

Peroxisome Proliferator Activated Receptor ◽

Iron Sulfur ◽

Promising Target

Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.

Download Full-text