p38α regulates SERCA2a function

Kaikkonen, Leena; Magga, Johanna; Ronkainen, Veli Pekka; Koivisto, Elina; Perjés, Ábel; Chuprun, J. Kurt; Vinge, Leif Erik; Kilpiö, Teemu; Aro, Jani; Ulvila, Johanna; Alakoski, Tarja; Bibb, James A.; Szokodi, István; Koch, Walter J.; Ruskoaho, Heikki; Kerkelä, Risto

doi:10.1016/j.yjmcc.2013.12.005

Cited by 22 publications

(23 citation statements)

References 34 publications

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“…In this regard, results from our study demonstrate a specific role of MK2, which may act directly or through its capacity to modulate the abundance of p38a (28,38). Interestingly, the specific inhibition of p38aMAPK, but not p38bMAPK, was recently shown (39) to enhance diastolic Ca 2+ uptake through increased PLB phosphorylation on the residue Ser16.…”

Section: Discussionmentioning

confidence: 51%

MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction

et al. 2015

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Heart disease remains a major complication of diabetes, and the identification of new therapeutic targets is essential. This study investigates the role of the protein kinase MK2, a p38 mitogen-activated protein kinase downstream target, in the development of diabetes-induced cardiomyopathy. Diabetes was induced in control (MK2(+/+)) and MK2-null (MK2(-/-)) mice using repeated injections of a low dose of streptozotocin (STZ). This protocol generated in MK2(+/+) mice a model of diabetes characterized by a 50% decrease in plasma insulin, hyperglycemia, and insulin resistance (IR), as well as major contractile dysfunction, which was associated with alterations in proteins involved in calcium handling. While MK2(-/-)-STZ mice remained hyperglycemic, they showed improved IR and none of the cardiac functional or molecular alterations. Further analyses highlighted marked lipid perturbations in MK2(+/+)-STZ mice, which encompass increased 1) circulating levels of free fatty acid, ketone bodies, and long-chain acylcarnitines and 2) cardiac triglyceride accumulation and ex vivo palmitate β-oxidation. MK2(-/-)-STZ mice were also protected against all these diabetes-induced lipid alterations. Our results demonstrate the benefits of MK2 deletion on diabetes-induced cardiac molecular and lipid metabolic changes, as well as contractile dysfunction. As a result, MK2 represents a new potential therapeutic target to prevent diabetes-induced cardiac dysfunction.

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Section: Discussionmentioning

confidence: 51%

MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction

et al. 2015

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“…Although the main phosphatase responsible for PLN dephosphorylation is protein phosphatase 1 (PP1), PLN dephosphorylation can also be mediated by protein phosphatase 2A (PP2A) [ 116 , 117 ]. p38 activation has been reported to promote PP2A translocation and activation in myocytes [ 118 ], and p38 inhibition reduces PP2A-mediated dephosphorylation of PLN [ 108 , 118 ]. Furthermore, PP2A activation could be the mechanism by which p38 activation inhibits the β-adrenergic receptor-mediated contractile response in cardiomyoctes [ 104 , 118 ].…”

Section: P38 In Heart Failure and Cardiac Arrhythmiamentioning

confidence: 99%

p38 MAPK Pathway in the Heart: New Insights in Health and Disease

Romero-Becerra

Santamans

Folgueira

et al. 2020

IJMS

102

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The p38 mitogen-activated kinase (MAPK) family controls cell adaptation to stress stimuli. p38 function has been studied in depth in relation to cardiac development and function. The first isoform demonstrated to play an important role in cardiac development was p38α; however, all p38 family members are now known to collaborate in different aspects of cardiomyocyte differentiation and growth. p38 family members have been proposed to have protective and deleterious actions in the stressed myocardium, with the outcome of their action in part dependent on the model system under study and the identity of the activated p38 family member. Most studies to date have been performed with inhibitors that are not isoform-specific, and, consequently, knowledge remains very limited about how the different p38s control cardiac physiology and respond to cardiac stress. In this review, we summarize the current understanding of the role of the p38 pathway in cardiac physiology and discuss recent advances in the field.

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“…In a recent randomized phase 2 trial in non-ST-segment elevation myocardial infarction, Newby et al observed that the use of a novel p38 mitogen-activated protein kinase inhibitor, losmapimod, was well tolerated in non-ST-segment elevation myocardial infarction patients and might improve outcomes after acute coronary syndromes [17]. Kaikkonen et al reported that negative p38α enhances SERCA2a function to improve cardiomyocyte contractility [18]. However, the exact mechanisms of the p38 MAPK pathway interacting with SERCA2a need to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion

Zhu

Luo

et al. 2017

Cell Physiol Biochem

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Background/Aims: A major challenge for current therapeutic strategies against ischemia/reperfusion (I/R) is the lack of effective drugs. Considering luteolin enhances the activity of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) to improve the systolic/diastolic function of rat hearts and cardiomyocytes during the I/R process, we studied the regulatory function of the p38 MAPK pathway in this protective mechanism. Methods: Isolated cardiomyocytes and perfused hearts were separately divided into five groups and used to investigate I/R. The phosphorylation of p38 and phospholamban (p-PLB), the levels and activity of SERCA2a and the levels of proteins related to apoptosis were measured. Apoptotic cells were assessed using the TUNEL assay. Single-cell shortening, Ca²⁺ transients, and the decay of the mitochondrial membrane potential (Δψm) were detected. Results: The p38 MAPK pathway was activated during the I/R process, and inhibiting it with SB203580 promoted p-PLB, which enhanced the activity of SERCA2a and relieved the calcium overload to promote the recovery of the Δψm and reduce cardiomyocyte apoptosis in I/R. Luteolin also suppressed the activation of the p38 MAPK pathway and showed cardioprotective effects during I/R injury. Conclusions: We conclude that luteolin enhances SERCA2a activity to improve systolic/diastolic function during I/R in rat hearts and cardiomyocytes by attenuating the inhibitive effects of the p38 pathway on p-PLB.

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p38α regulates SERCA2a function

Cited by 22 publications

References 34 publications

MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction

MK2 Deletion in Mice Prevents Diabetes-Induced Perturbations in Lipid Metabolism and Cardiac Dysfunction

p38 MAPK Pathway in the Heart: New Insights in Health and Disease

Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion

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