Calreticulin Induces Dilated Cardiomyopathy

Lee, Dukgyu; Oka, Tatsujiro; Hunter, Beth; Robinson, Alison; Papp, Sylvia; Nakamura, Kimitoshi; Srisakuldee, Wattamon; Nickel, Barbara E.; Light, Peter E.; Dyck, Jason R.B.; Lopaschuk, Gary D.; Kardami, Elissavet; Opas, Michał; Michalak, Marek

doi:10.1371/journal.pone.0056387

Cited by 27 publications

(46 citation statements)

References 48 publications

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“…The CALR protein is localized primarily in the endoplasmic reticulum through its C-terminal KDEL motif [3], but it is also found in the cell membrane, cytoplasm, and extracellular matrix [4,5]. Functionally, CALR is believed to participate in Ca2+ homeostasis as a calcium-binding protein, handling misfolded proteins, cell adhesion, immune response to cancer, and phagocytosis [4,6,7,8,9,10,11,12,13]. CALR-knockout mice are born dead and display impaired cardiac development, whereas postnatal overexpression also leads to cardiac defects [14,15].…”

Section: Introductionmentioning

confidence: 99%

The Mutation Profile of Calreticulin in Patients with Myeloproliferative Neoplasms and Acute Leukemia

Wang¹,

JianGuo²,

He³

et al. 2016

Tjh

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Objective:Calreticulin (CALR) plays important roles in cell proliferation, apoptosis, and immune responses. CALR mutations were described recently in Janus kinase 2 gene (JAK2)-negative or MPL-negative primary myelofibrosis (PMF) and essential thrombocythemia (ET) patients. CALR trails JAK2 as the second most mutated gene in myeloproliferative neoplasms (MPNs). However, little is known about CALR mutation in Chinese patients with leukemia. In the present study, a cohort of 305 Chinese patients with hematopoietic neoplasms was screened for CALR mutations, with the aim of uncovering the frequency of CALR mutations in leukemia and MPNs.Materials and Methods:Polymerase chain reaction and direct sequencing were performed to analyze mutations of CALR in 305 patients with hematopoietic malignancies, including 135 acute myeloid leukemia patients, 57 acute lymphoblastic leukemia patients, and 113 MPN patients.Results:CALR mutations were found in 10.6% (12 of 113) of samples from patients with MPNs. CALR mutations were determined in 11.3% (6 of 53), 21.7% (5 of 23), and 9.1% (1/11) of patients with ET, PMF, and unclassifiable MPN, respectively.Conclusion:We showed that MPN patients carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels compared to those with mutated JAK2. However, all of the leukemia patients had negative results for CALR mutations.

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Section: Introductionmentioning

confidence: 99%

The Mutation Profile of Calreticulin in Patients with Myeloproliferative Neoplasms and Acute Leukemia

Wang¹,

JianGuo²,

He³

et al. 2016

Tjh

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“…Conversely, cardiac-specific CRT overexpression could induce DCM characterized by impaired left ventricular systolic and diastolic function, complete heart block, and sudden death in mice [19,20]. Recently, we reported that CRT was significantly upregulated in the myocardium of a rat model of furazolidone-induced DCM, resulting in apparent mitochondrial dysfunction via CRT-STAT3 (signal transducer and activator of transcription 3) signaling pathway [11].…”

Section: Discussionmentioning

confidence: 99%

Calreticulin is localized at mitochondria of rat cardiomyocytes and affected by furazolidone

et al. 2014

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Calreticulin (CRT) is a calcium-buffering protein which is predominantly located in endoplasmic reticulum. In the previous mitochondria proteome analysis, we accidentally found that CRT may be also localized at myocardial mitochondria and was upregulated in a rat model of furazolidone-induced dilated cardiomyopathy. To our knowledge, there has not yet been any report of its presence in mitochondria of any cell types. The present study aimed to determine whether CRT was located at the mitochondria of rat cardiomyocytes and whether the mitochondrial CRT was affected by furazolidone. Mitochondrial preparations were isolated from primary cultured neonatal rat cardiomyocytes and purified by differential centrifugation. The purity of mitochondria was assessed by the reduction or elimination of the immunoreactivities of markers for cytosol, nucleus, sarcolemma, and endoplasmic reticulum. Western blot analysis demonstrated the presence of CRT in purified mitochondria of rat cardiomyocytes. The distribution of CRT to mitochondria was further confirmed by immuno-electron microscopy, flow cytometry, and laser scanning confocal microscopy (double staining with MitoTracker Red and CRT-Alexa Fluor 488). Western blot analysis also demonstrated that the mitochondrial content of CRT was significantly enhanced by furazolidone treatment by 2.73 ± 0.13 fold (P < 0.05) in rat cardiomyocytes, which was verified by immuno-electron microscopy. In summary, the present results suggest that CRT is localized at mitochondria of rat cardiomyocytes and such localization is affected by furazolidone.

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“…Animal studies revealed that forced induction of apoptosis in the mouse heart leads to DCM [10,11]. Accordingly, a caspase-8 transgenic mouse model that develops heart failure can be rescued by inhibition of apoptosis [10].…”

Section: Introductionmentioning

confidence: 99%

Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy

Zhou

Hahn

Neupane

et al. 2017

IJMS

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Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role of IER3 in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM). Transferase dUTP nick end labeling (TUNEL) and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, while IER3 response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting the IER3 pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure.

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Calreticulin Induces Dilated Cardiomyopathy

Cited by 27 publications

References 48 publications

The Mutation Profile of Calreticulin in Patients with Myeloproliferative Neoplasms and Acute Leukemia

The Mutation Profile of Calreticulin in Patients with Myeloproliferative Neoplasms and Acute Leukemia

Calreticulin is localized at mitochondria of rat cardiomyocytes and affected by furazolidone

Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy

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