MG132, a proteasome inhibitor, attenuates pressure-overload-induced cardiac hypertrophy in rats by modulation of mitogen-activated protein kinase signals

ABSTRACT The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38α is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38α in hearts. First, we generated mice with floxed p38α alleles and crossbred them with mice expressing the Cre recombinase under the control of the α-myosin heavy-chain promoter to obtain cardiac-specific p38α knockout mice. These cardiac-specific p38α knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38α plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.

Download Full-text

Modification of ischemia/reperfusion induced infarct size by ischemic preconditioning in hypertrophied hearts

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0400 ◽

2021 ◽

Vol 99 (2) ◽

pp. 218-223

Author(s):

Mohamad Nusier ◽

Mohammad Alqudah ◽

Vijayan Elimban ◽

Naranjan S. Dhalla

Keyword(s):

Protein Kinase ◽

Cardiac Hypertrophy ◽

Infarct Size ◽

P38 Mapk ◽

Ischemic Preconditioning ◽

Creatine Phosphokinase ◽

Ischemia Reperfusion ◽

Mitogen Activated Protein Kinase ◽

Normal Heart ◽

Mitogen Activated Protein

This study examined the effects of ischemic preconditioning (IP) on the ischemia/reperfusion (I/R) induced injury in normal and hypertrophied hearts. Cardiac hypertrophy in rabbits was induced by L-thyroxine (0.5 mg/kg/day for 16 days). Hearts with or without IP (3 cycles of 5 min ischemia and 10 min reperfusion) were subjected to I/R (60 min ischemia followed by 60 min reperfusion). IP reduced the I/R-induced infarct size from 68% to 24% and 57% to 33% in the normal and hypertrophied hearts, respectively. Leakage of creatine phosphokinase in the perfusate from the hypertrophied hearts due to I/R was markedly less than that form the normal hearts; IP prevented these changes. Although IP augmented the increase in phosphorylated p38-mitogen-activated protein kinase (p38-MAPK) content due to I/R, this effect was less in the hypertrophied than in the normal heart. These results suggest that reduced cardioprotection by IP of the I/R-induced injury in hypertrophied hearts may be due to reduced activation of p38-MAPK in comparison with normal hearts.

Download Full-text

Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin–NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways

Circulation Heart Failure ◽

10.1161/circheartfailure.117.003960 ◽

2017 ◽

Vol 10 (6) ◽

Cited By ~ 1

Author(s):

Wenjuan Liu ◽

Jianxin Deng ◽

Wenwen Ding ◽

Gang Wang ◽

Yuanyuan Shen ◽

...

Keyword(s):

T Cells ◽

Protein Kinase ◽

Cardiac Hypertrophy ◽

Mitogen Activated Protein Kinase ◽

Nuclear Factor ◽

Activated T Cells ◽

Mitogen Activated Protein

Download Full-text

Effects of Sodium Ferulate on Cardiac Hypertrophy Are via the CaSR-Mediated Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.674570 ◽

2021 ◽

Vol 12 ◽

Author(s):

Panpan Chen ◽

Zhaoqin Wen ◽

Wanlan Shi ◽

Zhongli Li ◽

Xiaoyan Chen ◽

...

Keyword(s):

Protein Kinase C ◽

Cardiovascular Diseases ◽

Protein Kinase ◽

Cardiac Hypertrophy ◽

Myosin Heavy Chain ◽

Heavy Chain ◽

Myocardial Hypertrophy ◽

Mitogen Activated Protein Kinase ◽

Kinase C ◽

Mitogen Activated Protein

As a common complication of many cardiovascular diseases, cardiac hypertrophy is characterized by increased cardiac cell volume, reorganization of the cytoskeleton, and the reactivation of fetal genes such as cardiac natriuretic peptide and β-myosin heavy chain. Cardiac hypertrophy is a distinguishing feature of some cardiovascular diseases. Our previous study showed that sodium ferulate (SF) alleviates myocardial hypertrophy induced by coarctation of the abdominal aorta, and these protective effects may be related to the inhibition of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling pathways. This study investigated the inhibitory effect and mechanism of SF on myocardial hypertrophy in spontaneously hypertensive rats (SHRs). The effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement, pathological analysis, and detection of atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) expression. To investigate the mechanisms underlying the anti-hypertrophic effects of SF, the calcium-sensing receptor (CaSR), calcineurin (CaN), nuclear factor of activated T cells 3 (NFAT3), zinc finger transcription factor 4 (GATA4), protein kinase C beta (PKC-β), Raf-1, extracellular signal-regulated kinase 1/2 (ERK 1/2), and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by molecular biology techniques. Treatment with SF ameliorated myocardial hypertrophy in 26-week-old SHRs. In addition, it downregulated the levels of ANP, β-MHC, CaSR, CaN, NFAT3, phosphorylated GATA4 (p-GATA4), PKC-β, Raf-1, and p-ERK 1/2; and upregulated the levels of p-NFAT3 and MKP-1. These results suggest that the effects of SF on cardiac hypertrophy are related to regulation of the CaSR-mediated signaling pathway.

Download Full-text

Stimulation of multiple MAPK pathways by mechanical overload in the perfused amphibian heart

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.5.r1689 ◽

2001 ◽

Vol 281 (5) ◽

pp. R1689-R1698 ◽

Cited By ~ 6

Author(s):

Ioanna-Katerina S. Aggeli ◽

Catherine Gaitanaki ◽

Antigone Lazou ◽

Isidoros Beis

Keyword(s):

Protein Kinase ◽

Signal Transduction Pathway ◽

Pressure Overload ◽

Mitogen Activated Protein Kinase ◽

Adaptive Responses ◽

Amphibian Species ◽

Mapk Pathways ◽

Mitogen Activated Protein ◽

Mechanical Overload ◽

Factor C

The mitogen-activated protein kinase (MAPK) signal transduction pathway activated by mechanical stress was investigated in the isolated perfused amphibian ( Rana ridibunda) heart. High perfusion pressure induced the rapid (30 s) and prolonged (30 min) phosphorylation of a p43-extracellular regulated kinase, a response almost completely inhibited by 25 μM PD-98059. c-Jun NH2-terminal kinase (JNK) was also phosphorylated with maximal values attained at 15 min and remained elevated over 30 min. In-gel kinase assays verified that phosphorylated JNKs are active, phosphorylating the transcription factor c-Jun. Furthermore, pressure overload rapidly stimulated the p38-MAPK phosphorylation (30 s), a transient process (5 min) abolished by 1 μM SB-203580. In-gel kinase assays revealed that with phosphorylation, active p38-MAPKs phosphorylate their substrate MAP kinase-activated protein kinase 2. Biochemical analysis along with immunohistochemical studies showed that with activation, the three MAPK subfamily members examined are localized not only in the cytoplasm but in the nucleus as well. Present results therefore demonstrate for the first time in an amphibian species the involvement of multiple MAPK pathways in the mechanical overload-induced adaptive responses of the heart as well as their possible physiological roles.

Download Full-text

β-Catenin Regulates Cardiac Energy Metabolism in Sedentary and Trained Mice

Life ◽

10.3390/life10120357 ◽

2020 ◽

Vol 10 (12) ◽

pp. 357

Author(s):

Volodymyr V. Balatskyi ◽

Oksana L. Palchevska ◽

Lina Bortnichuk ◽

Ana-Maria Gan ◽

Anna Myronova ◽

...

Keyword(s):

Protein Kinase ◽

Cardiac Hypertrophy ◽

Endurance Training ◽

Metabolic Regulation ◽

Training Model ◽

Cardiac Metabolism ◽

Mitogen Activated Protein Kinase ◽

Hypertrophic Growth ◽

Physiological Cardiac Hypertrophy ◽

Mitogen Activated Protein

The role of canonical Wnt signaling in metabolic regulation and development of physiological cardiac hypertrophy remains largely unknown. To explore the function of β-catenin in the regulation of cardiac metabolism and physiological cardiac hypertrophy development, we used mice heterozygous for cardiac-specific β-catenin knockout that were subjected to a swimming training model. β-Catenin haploinsufficient mice subjected to endurance training displayed a decreased β-catenin transcriptional activity, attenuated cardiomyocytes hypertrophic growth, and enhanced activation of AMP-activated protein kinase (AMPK), phosphoinositide-3-kinase–Akt (Pi3K–Akt), and mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2 (MAPK/Erk1/2) signaling pathways compared to trained wild type mice. We further observed an increased level of proteins involved in glucose aerobic metabolism and β-oxidation along with perturbed activity of mitochondrial oxidative phosphorylation complexes (OXPHOS) in trained β-catenin haploinsufficient mice. Taken together, Wnt/β-catenin signaling appears to govern metabolic regulatory programs, sustaining metabolic plasticity in adult hearts during the adaptation to endurance training.

Download Full-text