Effects of ERK1/2/PPARα/SCAD signal pathways on cardiomyocyte hypertrophy induced by insulin-like growth factor 1 and phenylephrine

Huang, Qiuju; Huang, Jinxian; Zeng, Zhenhua; Luo, Jiani; Liu, Peiqing; Liu, Bing; Pan, Xuediao; Zang, Lei; Zhou, Sigui

doi:10.1016/j.lfs.2015.01.015

Cited by 17 publications

(26 citation statements)

References 30 publications

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“…Down regulation of PPARαin cardiomyocytes is common to many types of hypertrophic stimuli [26,[36][37][38][39]. Consistent with earlier reports we have validated its causal relationship with the hypertrophic process by using its agonists, fenofibrate ( Fig.…”

Section: Discussionsupporting

confidence: 90%

Targeting Peroxisome Proliferator Activated Receptor α (PPAR α) for the Prevention of Mitochondrial Impairment and Hypertrophy in Cardiomyocytes

Kar

Bandyopadhyay²

2018

Cell Physiol Biochem

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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 (Δψ_m) 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.

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Section: Discussionsupporting

confidence: 90%

Targeting Peroxisome Proliferator Activated Receptor α (PPAR α) for the Prevention of Mitochondrial Impairment and Hypertrophy in Cardiomyocytes

Kar

Bandyopadhyay²

2018

Cell Physiol Biochem

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“…PPARα activation inhibits the cardiac expression of transforming necrosis factor-α partly by antagonizing nuclear NF-κB activity in neonatal rat cardiac myocytes [90]. Moreover, the decreased activation of protein kinases, such as extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, Akt, and glycogen synthase kinase 3 beta, may also contribute to the effect of PPARα on the heart [91][92][93][94][95][96].…”

Section: Pparα In Heart Injurymentioning

confidence: 99%

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

Yang

et al. 2018

Cell Physiol Biochem

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Three members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα, PPARγ, and PPARβ/δ, have been investigated widely over the past few decades. Although the roles of these PPARs and their agonists/antagonists were defined in clinical and basic studies, the conflicting results from these studies indicate that more analysis is needed to understand the roles of PPARs. PPARα is a ligand-activated transcription factor that contributes to the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. In this review, we focus on the function and mechanisms of PPARα in the cardiovascular system under various pathological conditions, including vascular and heart injury, blood pressure regulation, and lipid disorder-related cardiovascular injury, as well as its polymorphisms and pharmacogenetic associations with cardiovascular diseases. The anti-inflammatory effect of PPARα in cardiovascular injury is mainly through inhibition of pro-inflammatory signaling pathways and improvement of the lipid profile. Moreover, PPARα also modulates the activity of endothelial nitric oxide synthase and resets the renin-angiotensin system to regulate vascular tone. PPARα gene variants appear to be associated with some cardiovascular risk factors, such as higher plasma lipid levels, cardiac growth, and increased risk of coronary artery disease. Nowadays, novel PPARα drugs with broad safety margins and therapeutic potential for metabolic syndrome and cardiovascular diseases are being developed and applied in the clinical setting. The insights from the current review shed new light on areas of further study and provide a better understanding of the role of PPARα in cardiovascular diseases.

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“…Primary cultures of neonatal rat cardiomyocytes (NRCMs) were prepared with the method previously described . Two‐ to three‐day‐old Sprague–Dawley rats were obtained from the Laboratory Animal Center of Guangzhou University of Chinese Medicine.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis of total protein isolated from NRCMs was performed as previously described . Briefly, protein samples (30 or 50 μg) were separated in 10% and 15% SDS‐PAGE and blotted to PVDF membrane.…”

Section: Methodsmentioning

confidence: 99%

“…Peroxisome proliferator‐activated receptor‐α (PPARα), a member of fatty acid‐activated nuclear receptor family, was involved in the development of left ventrical hypertrophy and cardiomyocyte apoptosis . Previous studies have shown that SCAD gene was regulated by PPARα . AMP‐activated protein kinase (AMPK) is a crucial metabolic energy sensor and its activation has been reported to directly reflect with the heart against hypertrophy, ischaemic injury and cell death .…”

Section: Introductionmentioning

confidence: 99%

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Effects of short‐chain acyl‐CoA dehydrogenase on cardiomyocyte apoptosis

Zeng

Huang

Shu

et al. 2016

J Cellular Molecular Medi

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Short‐chain acyl‐CoA dehydrogenase (SCAD), a key enzyme of fatty acid β‐oxidation, plays an important role in cardiac hypertrophy. However, its effect on the cardiomyocyte apoptosis remains unknown. We aimed to determine the role of SCAD in tert‐butyl hydroperoxide (tBHP)‐induced cardiomyocyte apoptosis. The mRNA and protein expression of SCAD were significantly down‐regulated in the cardiomyocyte apoptosis model. Inhibition of SCAD with siRNA‐1186 significantly decreased SCAD expression, enzyme activity and ATP content, but obviously increased the content of free fatty acids. Meanwhile, SCAD siRNA treatment triggered the same apoptosis as cardiomyocytes treated with tBHP, such as the increase in cell apoptotic rate, the activation of caspase3 and the decrease in the Bcl‐2/Bax ratio, which showed that SCAD may play an important role in primary cardiomyocyte apoptosis. The changes of phosphonate AMP‐activated protein kinase α (p‐AMPKα) and Peroxisome proliferator‐activated receptor α (PPARα) in cardiomyocyte apoptosis were consistent with that of SCAD. Furthermore, PPARα activator fenofibrate and AMPKα activator AICAR treatment significantly increased the expression of SCAD and inhibited cardiomyocyte apoptosis. In conclusion, for the first time our findings directly demonstrated that SCAD may be as a new target to prevent cardiomyocyte apoptosis through the AMPK/PPARα/SCAD signal pathways.

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Effects of ERK1/2/PPARα/SCAD signal pathways on cardiomyocyte hypertrophy induced by insulin-like growth factor 1 and phenylephrine

Cited by 17 publications

References 30 publications

Targeting Peroxisome Proliferator Activated Receptor α (PPAR α) for the Prevention of Mitochondrial Impairment and Hypertrophy in Cardiomyocytes

Targeting Peroxisome Proliferator Activated Receptor α (PPAR α) for the Prevention of Mitochondrial Impairment and Hypertrophy in Cardiomyocytes

Targeting PPARα for the Treatment and Understanding of Cardiovascular Diseases

Effects of short‐chain acyl‐CoA dehydrogenase on cardiomyocyte apoptosis

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