Osteopontin stimulates apoptosis in adult cardiac myocytes via the involvement of CD44 receptors, mitochondrial death pathway, and endoplasmic reticulum stress

Dalal, Suman; Zha, Qinqin; Daniels, Christopher R.; Steagall, Rebecca J.; Joyner, William L.; Gadeau, Alain‐Pierre; Singh, Mahipal; Singh, Krishna

doi:10.1152/ajpheart.00954.2013

Cited by 38 publications

(52 citation statements)

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“…In streptozotocin-induced diabetic model, myocytes were identified as a source of OPN and myocyte apoptosis was significantly lower in mice lacking OPN (Subramanian et al, 2007). Likewise, cardiac myocyte-specific expression of OPN in the mouse heart during the first 11 weeks of life or in the adult heart led to increased myocyte apoptosis and myocardial dysfunction (Renault et al, 2010; Dalal et al, 2014). Myocardium of DCM patients associates with increased myocyte apoptosis (Di Napoli et al, 2003), where increased OPN expression in myocytes correlates negatively with heart function (Stawowy, et al, 2002).…”

Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

“…Myocardium of DCM patients associates with increased myocyte apoptosis (Di Napoli et al, 2003), where increased OPN expression in myocytes correlates negatively with heart function (Stawowy, et al, 2002). Recently, we provided evidence that treatment of adult rat cardiac myocytes with purified OPN protein or adenoviral-mediated expression of OPN in induces apoptosis (Dalal et al, 2014). However, the involvement of OPN in myocyte autophagy and necrosis requires further investigations.…”

Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

“…Proximity ligation assay, which identifies interactions between two proteins in their native form, confirmed interaction of OPN with CD44 receptors. Furthermore, neutralizing anti-CD44 antibodies inhibited OPN-stimulated apoptosis (Dalal et al, 2014). Taken together, these data suggested that OPN, most likely acting via CD44 receptor, induces apoptosis in myocyte.…”

Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

“…In adult rat cardiac myocytes, β-adrenergic receptor-stimulated induction of ER stress plays a pro-apoptotic role (Dalal et al, 2012). OPN-stimulated apoptosis in adult rat cardiac myocytes associates with activation of JNKs, increased Bax expression, decreased Bcl 2 /Bax ratio and increased levels of cytosolic cytochrome c (Dalal et al, 2014). It also associates with increased Gadd153 expression and activation of caspase-12.…”

Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

“…However, expression of OPN increases markedly in the heart under a variety of pathophysiological conditions (Singh et al, 2010a). Evidence has been provided that increased OPN expression, specifically in myocytes, associates with increased myocyte apoptosis and myocardial dysfunction (Subramanian et al, 2007; Renault et al, 2010; Dalal et al, 2014). While lack of OPN associates with reduced fibrosis in different models of myocardial hypertrophy and failure (Trueblood et al, 2001; Subramanian et al, 2007; Sam et al, 2004; Matsui et al, 2004), this review summarizes OPN expression in the heart, and its role in the induction of myocyte apoptosis and myocardial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Osteopontin: At the cross-roads of myocyte survival and myocardial function

2014

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Heart failure represents a major cause of morbidity and mortality in the western society. Cardiac myocyte loss due to apoptosis plays a significant role in the progression of heart failure. The extracellular matrix (ECM) maintains the structural integrity of the heart and allows the transmission of electrical and mechanical signals during cardiac contraction and relaxation. Matricellular proteins, a class of non-structural ECM proteins, play a significant role in ECM homeostasis and intracellular signaling via their interactions with cell surface receptors, structural proteins, and/or soluble extracellular factors such as growth factors and cytokines. Osteopontin (OPN), also called cytokine Eta-1, is a member of matricellular protein family. Normal heart expresses low levels of OPN. However, OPN expression increases markedly under a variety of pathophysiological conditions of the heart. Many human and transgenic mice studies provide evidence that increased OPN expression, specifically in myocytes, associates with increased myocyte apoptosis and myocardial dysfunction. This review summarizes OPN expression in the heart, and its role in myocyte apoptosis and myocardial function.

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Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

Section: Opn In Myocyte Apoptosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Osteopontin: At the cross-roads of myocyte survival and myocardial function

2014

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Targeting Osteopontin, the Silent Partner of Na⁺/H⁺ Exchanger Isoform 1 in Cardiac Remodeling

Mohamed

Mraiche

2015

Journal Cellular Physiology

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Cardiac hypertrophy (CH), characterized by the enlargement of cardiomyocytes, fibrosis and apoptosis, contributes to cardiac remodeling, which if left unresolved results in heart failure. Understanding the signaling pathways underlying CH is necessary to identify potential therapeutic targets. The Na(+) /H(+) -exchanger isoform I (NHE1), a ubiquitously expressed glycoprotein and cardiac specific isoform, regulates intracellular pH. Recent studies have demonstrated that enhanced expression/activity of NHE1 contributes to cardiac remodeling and CH. Inhibition of NHE1 in both in vitro and in vivo models have suggested that inhibition of NHE1 protects against hypertrophy. However, clinical trials using NHE1 inhibitors have proven to be unsuccessful, suggesting that additional factors maybe contributing to cardiac remodeling. Recent studies have indicated that the upregulation of NHE1 is associated with enhanced levels of osteopontin (OPN) in the setting of CH. OPN has been demonstrated to be upregulated in left ventricular hypertrophy, dilated cardiomyopathy and in diabetic cardiomyopathy. The cellular interplay between OPN and NHE1 in the setting of CH remains unknown. This review focuses on the role of NHE1 and OPN in cardiac remodeling and emphasizes the signaling pathways implicating OPN in the NHE1-induced hypertrophic response.

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Osteopontin-stimulated apoptosis in cardiac myocytes involves oxidative stress and mitochondrial death pathway: role of a pro-apoptotic protein BIK

et al. 2016

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Increased osteopontin (OPN) expression in the heart, specifically in myocytes, associates with increased myocyte apoptosis and myocardial dysfunction. Recently, we provided evidence that OPN interacts with CD44 receptor, and induces myocyte apoptosis via the involvement of endoplasmic reticulum stress and mitochondrial death pathways. Here we tested the hypothesis that OPN induces oxidative stress in myocytes and the heart via the involvement of mitochondria and NADPH oxidase−4 (NOX−4). Treatment of adult rat ventricular myocytes (ARVMs) with OPN (20 nM) increased oxidative stress as analyzed by protein carbonylation, and intracellular reactive oxygen species (ROS) levels as analyzed by ROS detection kit and dichlorohydrofluorescein diacetate staining. Pretreatment with NAC (antioxidant), apocynin (NOX inhibitor), MnTBAP (superoxide dismutase mimetic), and mitochondrial KATP channel blockers (glibenclamide and 5-hydroxydecanoate) decreased OPN-stimulated ROS production, cytosolic cytochrome c levels, and apoptosis. OPN increased NOX−4 expression, while decreasing SOD−2 expression. OPN decreased mitochondrial membrane potential as measured by JC−1 staining, and induced mitochondrial abnormalities including swelling and reorganization of cristae as observed using transmission electron microscopy. OPN increased expression of BIK, a pro-apoptotic protein involved in reorganization of mitochondrial cristae. Expression of dominant-negative BIK decreased OPN-stimulated apoptosis. In vivo, OPN expression in cardiac myocyte-specific manner associated with increased protein carbonylation, and expression of NOX−4 and BIK. Thus, OPN induces oxidative stress via the involvement of mitochondria and NOX−4. It may affect mitochondrial morphology and integrity, at least in part, via the involvement of BIK.

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Osteopontin stimulates apoptosis in adult cardiac myocytes via the involvement of CD44 receptors, mitochondrial death pathway, and endoplasmic reticulum stress

Cited by 38 publications

References 59 publications

Osteopontin: At the cross-roads of myocyte survival and myocardial function

Osteopontin: At the cross-roads of myocyte survival and myocardial function

Targeting Osteopontin, the Silent Partner of Na⁺/H⁺ Exchanger Isoform 1 in Cardiac Remodeling

Osteopontin-stimulated apoptosis in cardiac myocytes involves oxidative stress and mitochondrial death pathway: role of a pro-apoptotic protein BIK

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Osteopontin stimulates apoptosis in adult cardiac myocytes via the involvement of CD44 receptors, mitochondrial death pathway, and endoplasmic reticulum stress

Cited by 38 publications

References 59 publications

Osteopontin: At the cross-roads of myocyte survival and myocardial function

Osteopontin: At the cross-roads of myocyte survival and myocardial function

Targeting Osteopontin, the Silent Partner of Na+/H+ Exchanger Isoform 1 in Cardiac Remodeling

Osteopontin-stimulated apoptosis in cardiac myocytes involves oxidative stress and mitochondrial death pathway: role of a pro-apoptotic protein BIK

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Targeting Osteopontin, the Silent Partner of Na⁺/H⁺ Exchanger Isoform 1 in Cardiac Remodeling