Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice

Talukder, Milton; Kalyanasundaram, Anuradha; Zuo, Li; Murugesan, V.; Nishijima, Yoshinori; Periasamy, Muthu; Zweíer, Jay L.

doi:10.1152/ajpheart.01016.2007

Cited by 57 publications

(54 citation statements)

References 51 publications

(77 reference statements)

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“…Cholesterol also can affect SERCA expression (58) and may accumulate excessively in CF lung (59). In one model, heterozygous SERCA2 knockout (SERCA2a 1/2 ) mice showed substantially enlarged infarction after cardiac ischemia (60). In addition, they showed impaired postischemic myocardial relaxation and reduced postischemic myocardial contractile function.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Expression in Cystic Fibrosis Airways

Ahmad¹,

Ahmad²,

Dremina³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Modulation of the activity of sarcoendoplasmic reticulum calcium ATPase (SERCA) can profoundly affect Ca 21 homeostasis. Although altered calcium homeostasis is a characteristic of cystic fibrosis (CF), the role of SERCA is unknown. Objectives: This study provides a comprehensive investigation of expression and activity of SERCA in CF airway epithelium. A detailed study of the mechanisms underlying SERCA changes and its consequences was also undertaken. Methods: Lung tissue samples (bronchus and bronchiole) from subjects with and without CF were evaluated by immunohistochemistry. Protein and mRNA expression in primary non-CF and CF cells was determined by Western and Northern blots. Measurements and Main Results: SERCA2 expression was decreased in bronchial and bronchiolar epithelia of subjects with CF. SERCA2 expression in lysates of polarized tracheobronchial epithelial cells from subjects with CF was decreased by 67% as compared with those from subjects without CF. Several non-CF and CF airway epithelial cell lines were also probed. SERCA2 expression and activity were consistently decreased in CF cell lines. Adenoviral expression of mutant F508 cystic fibrosis transmembrane regulator gene (CFTR), inhibition of CFTR function pharmacologically (CFTR inh 172), or stable expression of antisense oligonucleotides to inhibit CFTR expression caused decreased SERCA2 expression. In CF cells, SERCA2 interacted with Bcl-2, leading to its displacement from caveolae-related domains of endoplasmic reticulum membranes, as demonstrated in sucrose density gradient centrifugation and immunoprecipitation studies. Knockdown of SERCA2 using siRNA enhanced epithelial cell death due to ozone, hydrogen peroxide, and TNF-a. Conclusions: Reduced SERCA2 expression may alter calcium signaling and apoptosis in CF. These findings decrease the likelihood of therapeutic benefit of SERCA inhibition in CF.

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Section: Discussionmentioning

confidence: 99%

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Expression in Cystic Fibrosis Airways

Ahmad¹,

Ahmad²,

Dremina³

et al. 2009

Am J Respir Crit Care Med

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“…At day 14 after tumor/PBS inoculation, in vivo cardiac contractile function was evaluated by transthoracic two-dimensional (2D) and M-mode echocardiography (17). Echocardiography was performed using a GE Vivid7 ultrasound system (GE, Waukesha, WI) with a linear probe (Model i13L; frequency 14 MHz).…”

Section: Methodsmentioning

confidence: 99%

Cardiac alterations in cancer-induced cachexia in mice

et al. 2010

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Abstract. Cachexia is a common syndrome in advanced cancer patients and causes up to 22% of cancer-related deaths. It remains elusive whether cancer cachexia causes heart failure. We investigated the effect of cancer cachexia on heart function and cardiac muscle structure in a mouse model. Male CD2F1 mice were inoculated with either colon-26 adenocarcinoma cells (Tumor group) or vehicle (PBS) (No Tumor group and Pair-fed group). Heart function as measured by fractional shortening in vivo using transthoracic echocardiography was performed on day 14 after tumor or PBS inoculation. At necropsy (day 17), hearts were collected for histology, transmission electron microscopy, RT-PCR and SDS-PAGE analysis. Mice from the Tumor group displayed a significantly reduced fractional shortening compared to mice in the No Tumor and Pair-fed groups. In hearts of the Tumor mice compared to the other groups, there was marked fibrosis and transmission electron microscopy revealed disrupted myocardial ultrastructure. Gene expression of troponin I, a regulator of cardiac muscle contraction, was reduced. Moreover, both mRNA and protein levels of myosin heavy chain (MHC) were altered whereby MHC· (adult isoform) was decreased and MHCß (fetal isoform) was increased indicating reactivation of the fetal gene expression pattern. In conclusion, heart function was diminished in mice with tumorinduced cachexia, and this impaired function was associated with increased fibrosis, disrupted myocardial structure and altered composition of contractile proteins of cardiac muscle.

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“…In this way, a SERCA2 deficiency would promote diastolic dysfunction and tachycardia. Studies of mice with a genetic deletion of one SERCA2 allele have demonstrated the importance of ER Ca 2ϩ uptake in protecting cardiac myocytes against ischemic injury in a model of myocardial infarction (Talukder et al, 2008).…”

Section: A Cardiac Cellsmentioning

confidence: 99%

Endoplasmic Reticulum Ca²⁺Handling in Excitable Cells in Health and Disease

2011

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Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice

Cited by 57 publications

References 51 publications

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Expression in Cystic Fibrosis Airways

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Expression in Cystic Fibrosis Airways

Cardiac alterations in cancer-induced cachexia in mice

Endoplasmic Reticulum Ca²⁺Handling in Excitable Cells in Health and Disease

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Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice

Cited by 57 publications

References 51 publications

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase Expression in Cystic Fibrosis Airways

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase Expression in Cystic Fibrosis Airways

Cardiac alterations in cancer-induced cachexia in mice

Endoplasmic Reticulum Ca2+Handling in Excitable Cells in Health and Disease

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Product

Resources

About

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Expression in Cystic Fibrosis Airways

Bcl-2 Suppresses Sarcoplasmic/Endoplasmic Reticulum Ca²⁺-ATPase Expression in Cystic Fibrosis Airways

Endoplasmic Reticulum Ca²⁺Handling in Excitable Cells in Health and Disease