Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy

Cipolletta, Ersilia; Rusciano, Maria Rosaria; Maione, Angela Serena; Santulli, Gaetano; Sorriento, Daniela; Giudice, Carmine Del; Ciccarelli, Michele; Franco, Antonietta; Crola, Catherine; Campiglia, Pietro; Sala, Marina; Gómez-Monterrey, Isabel; Luca, Nicola De; Trimarco, Bruno; Iaccarino, Guido; Illario, Maddalena

doi:10.1371/journal.pone.0130477

Cited by 56 publications

(44 citation statements)

References 62 publications

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“…5A, Lower lists the corresponding ratios that are elevated only on a hard, plastic surface. Each of the proteins whose phosphorylation is up-regulated in NMIIA-deleted GBM cells on a soft surface is connected to the Ras-Raf-MEK-ERK pathway (31)(32)(33)(34)(35)(36). Western blots of these lysates demonstrate that when grown on a soft (0.5 kPa) substrate, NMIIA-deleted cells enhance ERK1/2 phosphorylation approximately fourfold compared with NMIIA-intact cells.…”

Section: A Retrovirally Driven Murine Model Of Gbm Provides a Way Tomentioning

confidence: 98%

Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner

Picariello

Kenchappa

Rai

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The ability of glioblastoma to disperse through the brain contributes to its lethality, and blocking this behavior has been an appealing therapeutic approach. Although a number of proinvasive signaling pathways are active in glioblastoma, many are redundant, so targeting one can be overcome by activating another. However, these pathways converge on nonredundant components of the cytoskeleton, and we have shown that inhibiting one of these—the myosin II family of cytoskeletal motors—blocks glioblastoma invasion even with simultaneous activation of multiple upstream promigratory pathways. Myosin IIA and IIB are the most prevalent isoforms of myosin II in glioblastoma, and we now show that codeleting these myosins markedly impairs tumorigenesis and significantly prolongs survival in a rodent model of this disease. However, while targeting just myosin IIA also impairs tumor invasion, it surprisingly increases tumor proliferation in a manner that depends on environmental mechanics. On soft surfaces myosin IIA deletion enhances ERK1/2 activity, while on stiff surfaces it enhances the activity of NFκB, not only in glioblastoma but in triple-negative breast carcinoma and normal keratinocytes as well. We conclude myosin IIA suppresses tumorigenesis in at least two ways that are modulated by the mechanics of the tumor and its stroma. Our results also suggest that inhibiting tumor invasion can enhance tumor proliferation and that effective therapy requires targeting cellular components that drive both proliferation and invasion simultaneously.

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Section: A Retrovirally Driven Murine Model Of Gbm Provides a Way Tomentioning

confidence: 98%

Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner

Picariello

Kenchappa

Rai

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Alterations in ECM composition and turnover are involved in different cardiac diseases characterized by adverse remodeling with loss of myocardium integrity (Swynghedauw, 1999;Aggeli et al, 2012;Santulli et al, 2012;Cipolletta et al, 2015). Patients affected by idiopathic dilated cardiomyopathy are characterized by an excessive deposition of collagen type III fibers that are poorly cross-linked and lead to cell slippage, ventricular dilatation, and altered diastolic compliance (Gunja-Smith et al, 1996).…”

Section: Cardiac Extracellular Matrix Regulationmentioning

confidence: 99%

Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

et al. 2020

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Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder, predisposing to malignant ventricular arrhythmias leading to sudden cardiac death, particularly in young and athletic patients. Pathological features include a progressive loss of myocardium with fibrous or fibro-fatty substitution. During the last few decades, different clinical aspects of ACM have been well investigated but still little is known about the molecular mechanisms that underlie ACM pathogenesis, leading to these phenotypes. In about 50% of ACM patients, a genetic mutation, predominantly in genes that encode for desmosomal proteins, has been identified. However, the mutation-associated mechanisms, causing the observed cardiac phenotype are not always clear. Until now, the attention has been principally focused on the study of molecular mechanisms that lead to a prominent myocardium adipose substitution, an uncommon marker for a cardiac disease, thus often recognized as hallmark of ACM. Nonetheless, based on Task Force Criteria for the diagnosis of ACM, cardiomyocytes death associated with fibrous replacement of the ventricular free wall must be considered the main tissue feature in ACM patients. For this reason, it urges to investigate ACM cardiac fibrosis. In this review, we give an overview on the cellular effectors, possible triggers, and molecular mechanisms that could be responsible for the ventricular fibrotic remodeling in ACM patients.

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“…This cell line has been used extensively as a model for ischemia/reperfusion injury 22–26 due to its high sensitivity to ischemia/reperfusion injury in terms of cell viability and mitochondrial respiration 24 . Moreover, H9c2 cells have been used in a number of studies involving CaMKII 27–30 . In these studies, the chronic exposure to all-trans retinoic acid was used to induce H9c2 cells to differentiate from cardiomyoblast-like to cardiomyocyte-like cells as has been previously described 31 .…”

Section: Introductionmentioning

confidence: 99%

Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury

Wongrakpanich

Morris

Geary

et al. 2017

International Journal of Pharmaceutics

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An excess of calcium (Ca2+) influx into mitochondria during mitochondrial re-energization is one of the causes of myocardial cell death during ischemic/reperfusion injury. This overload of Ca2+ triggers the mitochondrial permeability transition pore (mPTP) opening which leads to programmed cell death. During the ischemic/reperfusion stage, the activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) enzyme is responsible for Ca2+ influx. To reduce CaMKII-related cell death, sub-micron particles composed of poly(lactic-co-glycolic acid) (PLGA), loaded with a CaMKII inhibitor peptide were fabricated. The CaMKII inhibitor peptide-loaded (CIP) particles were coated with a mitochondria targeting moiety, triphenylphosphonium cation (TPP), which allowed the particles to accumulate and release the peptide inside mitochondria to inhibit CaMKII activity. The fluorescently labeled TPP-CIP were taken up by mitochondria and successfully reduced ROS caused by Isoprenaline (ISO) in a differentiated rat cardiomyocyte-like cell line. When cells were treated with TPP-CIP prior ISO exposure, they maintained mitochondrial membrane potential. The TPP-CIP protected cells from ISO-induced ROS production and decreased mitochondrial membrane potential. Thus, TPP-CIP have the potential to be used in protection against ischemia/reperfusion injury.

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Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy

Cited by 56 publications

References 62 publications

Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner

Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner

Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury

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