Impaired angiotensin II–extracellular signal-regulated kinase signaling in failing human ventricular myocytes

Modesti, Pietro Amedeo; Serneri, Gian Gastone Neri; Gamberi, Tania; Boddi, Maria; Coppo, Mirella; Lucchese, Gianluca; Chiavarelli, Mario; Bottai, Giulia; Marino, F; Gensini, Camilla Toz; Gensini, Gian Franco; Modesti, Alessandra

doi:10.1097/hjh.0b013e328308de68

Cited by 6 publications

(3 citation statements)

References 48 publications

(75 reference statements)

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“…MAPK signaling cascade consists of extracellular-regulated kinases (ERK), c-Jun NH2-terminal kinases (JNKs) and p38 MAPK (Sopontammarak et al 2005). Previous studies analyzing MAPK activities in cardiac hypertrophy have demonstrated differential effects; in that, persistent activation of p38 and JNK can promote apoptosis, resulting in cardiac dilation and dysfunction (Pearson et al 2001), whereas ERK1/2 has been proposed to regulate smooth muscle contraction and to promote cellular hypertrophy (Modesti et al 2008;Pearson et al 2001;Sopontammarak et al 2005).…”

Section: Introductionmentioning

confidence: 98%

5-, 12- and 15-Hydroxyeicosatetraenoic acids induce cellular hypertrophy in the human ventricular cardiomyocyte, RL-14 cell line, through MAPK- and NF-κB-dependent mechanism

Maayah

El‐Kadi

2015

Arch Toxicol

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Recent studies have established the role of mid-chain hydroxyeicosatetraenoic acids (HETEs) in the development of cardiovascular disease. Mid-chain HETEs have been reported to have vasoconstrictive and pro-inflammatory effects. However, whether mid-chain HETEs can induce cardiac hypertrophy remains unclear. Therefore, the overall objective of the present study was to elucidate the potential hypertrophic effect of mid-chain HETEs in the human ventricular cardiomyocytes, RL-14 cells, and to explore the mechanisms involved. For this purpose, RL-14 cells were treated with increasing concentrations of mid-chain HETEs (2.5, 5, 10 and 20 µM). Thereafter, the cardiac hypertrophy markers and cell size were determined using real-time polymerase chain reaction and phase contrast imaging, respectively. Phosphorylated mitogen-activated protein kinase (MAPK) level and nuclear factor kappa B (NF-κB) binding activity were determined. Our results showed that mid-chain HETEs induced cellular hypertrophy in RL-14 cells as evidenced by the induction of cardiac hypertrophy markers, α- and β-myocin heavy chain and atrial and brain natriuretic peptide as well as the increase in cell size. Mechanistically, all mid-chain HETEs were able to induce the binding activity of NF-κB to its responsive element in a HETE-dependent manner, and they significantly induced the phosphorylation of ERK 1/2. The induction of cellular hypertrophy was associated with proportional increase in the formation of dihydroxyeicosatrienoic acids parallel to the increase of soluble epoxide hydrolase enzyme activity. In conclusion, our study provides the first evidence that mid-chain HETEs induce cellular hypertrophy in RL-14 cells through MAPK- and NF-κB-dependent mechanism.

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Section: Introductionmentioning

confidence: 98%

5-, 12- and 15-Hydroxyeicosatetraenoic acids induce cellular hypertrophy in the human ventricular cardiomyocyte, RL-14 cell line, through MAPK- and NF-κB-dependent mechanism

Maayah

El‐Kadi

2015

Arch Toxicol

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“…7 JAK2 response to Angiotensin (Ang)II was found to be enhanced in human failing cardiomyocytes, where conversely ERK1/2 response to Ang II was reported to be impaired. 9 However, information regarding events downstream JAK2 in human failing cardiomyocytes, and in particular the STATs response to Ang II, is lacking. The signaling pathway activated by JAK2 may indeed lead to different final responses depending on the selective phosphorylation of different elements of the STAT family.…”

Section: Introductionmentioning

confidence: 99%

“…9 However, information regarding events downstream JAK2 in human failing cardiomyocytes, and in particular the STATs response to Ang II, is lacking. The signaling pathway activated by JAK2 may indeed lead to different final responses depending on the selective phosphorylation of different elements of the STAT family.…”

Section: Introductionmentioning

confidence: 99%

Impaired JAK2-induced activation of STAT3 in failing human myocytes

et al. 2012

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Although angiotensin (Ang)II-induced Janus-activated kinase (JAK)2 phosphorylation was reported to be enhanced in failing human cardiomyocytes, the downstream balance between cardio-protective (signal transducer and activator of transcription-STAT3) and the pro-inflammatory (STAT2 and STAT5) response remains unexplored. Therefore STATs phosphorylation and putative genes overexpression following JAK2 activation were investigated in isolated cardiomyocytes obtained from failing human hearts (n = 16), and from non-failing(NF) hearts of humans (putative donors, n = 6) or adult rats. In NF myocytes Ang II-induced JAK2 activation was followed by STAT3 phosphorylation (186 AE 45% at 30 min), with no STAT2 or STAT5 response. The associated B cell lymphoma (Bcl)-xL overexpression (1.05 AE 0.39 fold) was abolished by both JAK2 and extracellular signal-regulated kinase (ERK)1/2 inhibitors (AG490, 10 mM, and PD98059, 30 mM, respectively), whereas Fas ligand (Fas-L) response (0.91 AE 0.21 fold) was inhibited only by p38MAPK antagonism (SB203580, 10 mM). In failing myocytes Ang II-induced JAK2 activation was followed by STAT2 (237 AE 38%) and STAT5 (222 AE 31%) phosphorylation, with no STAT3 response. No changes in Bcl-xL expression were observed, and the associated Fas-L gene overexpression (1.14 AE 0.27 fold) being abolished by p38 mitogen-activated protein kinase (MAPK) antagonism. The altered JAK2 induced STATs response in human failing cardiomyocytes may be of relevance for the progression of cardiac dysfunction in heart failure.

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The role of mid-chain hydroxyeicosatetraenoic acids in the pathogenesis of hypertension and cardiac hypertrophy

Maayah

El‐Kadi

2015

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The incidence, prevalence, and hospitalization rates associated with cardiovascular diseases (CVDs) are projected to increase substantially in the world. Understanding of the biological and pathophysiological mechanisms of survival can help the researchers to develop new management modalities. Numerous experimental studies have demonstrated that mid-chain HETEs are strongly involved in the pathogenesis of the CVDs. Mid-chain HETEs are biologically active eicosanoids that result from the metabolism of arachidonic acid (AA) by both lipoxygenase and CYP1B1 (lipoxygenase-like reaction). Therefore, identifying the localizations and expressions of the lipoxygenase and CYP1B1 and their associated AA metabolites in the cardiovascular system is of major importance in understanding their pathological roles. Generally, the expression of these enzymes is shown to be induced during several CVDs, including hypertension and cardiac hypertrophy. The induction of these enzymes is associated with the generation of mid-chain HETEs and subsequently causation of cardiovascular events. Of interest, inhibiting the formation of mid-chain HETEs has been reported to confer a protection against different cardiac hypertrophy and hypertension models such as angiotensin II, Goldblatt, spontaneously hypertensive rat and deoxycorticosterone acetate (DOCA)-salt-induced models. Although the exact mechanisms of mid-chain HETEs-mediated cardiovascular dysfunction are not fully understood, the present review proposes several mechanisms which include activating G-protein-coupled receptor, protein kinase C, mitogen-activated protein kinases, and nuclear factor kappa B. This review provides a clear understanding of the role of mid-chain HETEs in the pathogenesis of cardiovascular diseases and their importance as novel targets in the treatment for hypertension and cardiac hypertrophy.

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Impaired angiotensin II–extracellular signal-regulated kinase signaling in failing human ventricular myocytes

Cited by 6 publications

References 48 publications

5-, 12- and 15-Hydroxyeicosatetraenoic acids induce cellular hypertrophy in the human ventricular cardiomyocyte, RL-14 cell line, through MAPK- and NF-κB-dependent mechanism

5-, 12- and 15-Hydroxyeicosatetraenoic acids induce cellular hypertrophy in the human ventricular cardiomyocyte, RL-14 cell line, through MAPK- and NF-κB-dependent mechanism

Impaired JAK2-induced activation of STAT3 in failing human myocytes

The role of mid-chain hydroxyeicosatetraenoic acids in the pathogenesis of hypertension and cardiac hypertrophy

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