Defining new mechanistic roles for αII spectrin in cardiac function

Lubbers, Ellen R.; Murphy, Nathaniel P.; Musa, Hassan; Huang, Claire Yu-Mei; Gupta, Rohan; Price, Morgan V.; Han, Mei; Daoud, Georges; Gratz, Daniel; Refaey, Mona El; Xu, Xianyao; Hoeflinger, Nicole K.; Friel, Emma L.; Lancione, Peter J.; Wallace, Michael J.; Cavus, Omer; Simmons, Samantha L.; Williams, Jeremy C.; Skaf, Michel; Koenig, Sara N.; Janssen, Paul M.L.; Rasband, Matthew N.; Hund, Thomas J.; Mohler, Peter J.

doi:10.1074/jbc.ra119.007714

Cited by 10 publications

(10 citation statements)

References 52 publications

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“…In ventricular myocytes, αII and βII spectrin are found at the transversetubule and sarcoplasmic reticulum membranes 8 , whereas βIV spectrin is located at the intercalated disc 30 . The three spectrins have been reported to play important roles in cardiovascular electrophysiology 12,30,31,32 . However, cardiomyocyte-selective αII spectrin-de cient mice display cardiomyocyte hypertrophy and cardiac brosis 31 .…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Cardiomyocyte βII Spectrin Plays a Critical Role in Maintaining Cardiac Function via Regulating Mitochondrial Respiratory Function

Wang

Yang

Ruan

et al. 2022

Preprint

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βII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, roles of βII spectrin in cardiac contractile function and post-myocardial infarction pathological remodeling remain unclear. Here, we uncovered that the levels of serum βII spectrin breakdown products (βII SBDPs) were significantly increased in patients with acute myocardial infarction. Consistently, βII spectrin was degraded into βII SBDPs by calpain in mouse hearts after ischemia/reperfusion (I/R) injury. Cardiac-specific βII spectrin deletion results in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy and fibrosis. Moreover, deletion of βII spectrin in the adult heart exacerbated I/R-induced cardiomyocyte death and heart failure, while restoration of βII spectrin expression by adenoviral saRNA delivery in the heart reduced I/R injury. IP–LC–MS/MS and functional studies revealed that βII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, βII spectrin interacted with mitochondrial complex I to mediate its assembly by crosslinking with actin filaments (F-actin) to maintain F-actin stability. These findings identify βII spectrin as an essential mitochondrial cytoskeletal element for preserving mitochondrial homeostasis and cardiac function.

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Cardiomyocyte βII Spectrin Plays a Critical Role in Maintaining Cardiac Function via Regulating Mitochondrial Respiratory Function

Wang

Yang

Ruan

et al. 2022

Preprint

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“…The same correlation has been seen in traumatic brain injuries and hypoxic‐ischaemic brain injury models, 33,34 . Alpha II‐spectrin is a protein that is essential for maintaining the integrity of brain cells, as it provides a link between the cytoskeleton and the plasma membrane 35 . It is a novel biomarker for neonatal HIE.…”

Section: Discussionmentioning

confidence: 66%

“… 33 , 34 Alpha II‐spectrin is a protein that is essential for maintaining the integrity of brain cells, as it provides a link between the cytoskeleton and the plasma membrane. 35 It is a novel biomarker for neonatal HIE. It is notable that the present data are in line with suggestions that alpha II‐spectrin might be a promising biomarker of brain injuries in infants following cardiac operations 36 and in paediatric traumatic brain injuries.…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study

et al. 2022

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Aim Perinatal asphyxia, resulting in hypoxic‐ischaemic encephalopathy (HIE), has been associated with high mortality rates and severe lifelong neurodevelopmental disabilities. Our aim was to study the association between the proteomic profile in cerebrospinal fluid (CSF) and the degree of HIE and long‐term outcomes. Methods We prospectively enrolled 18‐term born infants with HIE and 10‐term born controls between 2000 and 2004 from the Karolinska University Hospital. An antibody suspension bead array and FlexMap3D analysis was used to characterise 178 unique brain‐derived and inflammation associated proteins in their CSF. Results Increased CSF concentrations of several brain‐specific proteins were observed in the proteome of HIE patients compared with the controls. An upregulation of neuroinflammatory pathways was also noted and this was confirmed by pathway analysis. Principal component analysis revealed a gradient from favourable to unfavourable HIE grades and outcomes. The proteins that provided strong predictors were structural proteins, including myelin basic protein and alpha‐II spectrin. The functional proteins included energy‐related proteins like neuron‐specific enolase and synaptic regulatory proteins. Increased CSF levels of 51 proteins correlated with adverse outcomes in infants with HIE. Conclusion Brain‐specific proteins and neuroinflammatory mediators in CSF may predict HIE degrees and outcomes after perinatal asphyxia.

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“…Interestingly, α II -spectrin also experiences protein loss in HF, while mouse models of cardiac specific deletion of α II -spectrin increases fibrosis at baseline and disease states (20), reflecting states of remodeling consistent with β IV -spectrin loss. Despite this, it is not clear what role α II -spectrin might play in the CaMKIIdependent degradation of β IV -spectrin and subsequent fibrotic remodeling.…”

Section: Discussionmentioning

confidence: 99%

Ca2+/calmodulin kinase II–dependent regulation of βIV-spectrin modulates cardiac fibroblast gene expression, proliferation, and contractility

Nassal

Patel

Unudurthi

et al. 2021

Journal of Biological Chemistry

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Defining new mechanistic roles for αII spectrin in cardiac function

Cited by 10 publications

References 52 publications

WITHDRAWN: Cardiomyocyte βII Spectrin Plays a Critical Role in Maintaining Cardiac Function via Regulating Mitochondrial Respiratory Function

WITHDRAWN: Cardiomyocyte βII Spectrin Plays a Critical Role in Maintaining Cardiac Function via Regulating Mitochondrial Respiratory Function

Proteomic profiles in cerebrospinal fluid predicted death and disability in term infants with perinatal asphyxia: A pilot study

Ca2+/calmodulin kinase II–dependent regulation of βIV-spectrin modulates cardiac fibroblast gene expression, proliferation, and contractility

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