Cardiomyocytes with disrupted CFTR function require CaMKII and Ca<sup>2+</sup>‐activated Cl<sup>−</sup> channel activity to maintain contraction rate

Sellers, Zachary M.; Arcangelis, Vania De; Xiang, Yang; Best, Philip M.

doi:10.1113/jphysiol.2010.188334

Cited by 42 publications

(48 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, simulation studies by Kuzumoto et al predicted that increases or decreases in CFTR channel density would positively or negatively alter action potential duration, respectively, due to β-adrenergic stimulation [4]. Our prior studies examining the effects of increasing or decreasing CFTR activity on isolated cardiomyocyte contraction support these predictions [5, 6]. Beyond maintaining normal physiologic function, CFTR is up-regulated during ischemia [7], involved in the protection of ischemic pre- and post-conditioning [8, 9], and down-regulated in patients with heart failure [10].…”

Section: Introductionsupporting

confidence: 54%

“…In the gut-corrected null mouse, human CFTR mRNA was detected throughout the intestinal tract, pancreas, kidney, and brain, but not in the heart [17]. In our prior experiments with gut-corrected ΔF508 mice, we did not observe any CFTR activity in isolated cardiac myocytes, as evidenced by the inability of CFTR inh -172 to affect contraction or Ca 2+ signaling [5]. …”

Section: Methodsmentioning

confidence: 99%

“…Recent evidence for increased aortic stiffness in CF children [12] and adults [13-15] has added to the question whether left ventricular dysfunction exists in CF. These studies, coupled with our prior experiments showing CFTR involvement in murine cardiomyocyte contraction [5, 6] led us to hypothesize that loss of CFTR function would lead to primary cardiovascular disturbances independent of lung disease. To bypass the effects of lung disease, we utilized ΔF508 CFTR mutant mice, which do not display the lung pathology found in CF patients [16, 17].…”

Section: Introductionmentioning

confidence: 95%

See 2 more Smart Citations

Left ventricular and aortic dysfunction in cystic fibrosis mice

Sellers

Kovács

Weinheimer

et al. 2013

Journal of Cystic Fibrosis

Self Cite

View full text Add to dashboard Cite

Background Left ventricular (LV) abnormalities have been reported in cystic fibrosis (CF); however, it remains unclear if loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes heart defects independent of lung disease. Methods Using gut-corrected F508del CFTR mutant mice (ΔF508), which do not develop human lung disease, we examined in vivo heart and aortic function via 2D transthoracic echocardiography and LV catheterization. Results ΔF508 mouse hearts showed LV concentric remodeling along with enhanced inotropy (increased +dP/dt, fractional shortening, decreased isovolumetric contraction time) and greater lusitropy (−dP/dt, Tau). Aortas displayed increased stiffness and altered diastolic flow. β-adrenergic stimulation revealed diminished cardiac reserve (attenuated +dP/dt,−dP/dt, LV pressure). Conclusions In a mouse model of CF, CFTR mutation leads to LV remodeling with alteration of cardiac and aortic functions in the absence of lung disease. As CF patients live longer, more active lives, their risk for cardiovascular disease should be considered.

show abstract

Section: Introductionsupporting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Left ventricular and aortic dysfunction in cystic fibrosis mice

Sellers

Kovács

Weinheimer

et al. 2013

Journal of Cystic Fibrosis

Self Cite

View full text Add to dashboard Cite

show abstract

“…Another possible mechanism is that, as occurs in other organs affected by CF, there is a direct involvement of the disease on the heart. Recently, it has been demonstrated that CFTR is involved in the regulation of cardiomyocyte contraction, and it has also been postulated that loss of CFTR function might leave CF patients at increased risk of heart dysfunction and disease [37]. Any direct involvement of the CF on the heart would be masked in advanced stages of the disease, when changes secondary to pulmonary hypertension and hypoxia would predominate.…”

Section: Discussionmentioning

confidence: 98%

Right ventricular dysfunction in adolescents with mild cystic fibrosis

Baño-Rodrigo

Salcedo-Posadas

Villa-Asensi

et al. 2012

Journal of Cystic Fibrosis

View full text Add to dashboard Cite

show abstract

“…Indeed, absence of a cardiac effect of the mutant CFTR on the heart is supported by similar graft survival of hearts obtained from donors with cystic fibrosis during a domino heart transplan tation, and hearts obtained from donors without cystic fibrosis 122 . Conversely, heart tissue expresses a unique splicing variant of CFTR 123 , and in vitro cardio myocyte prepar ations from Cftr −/− mice lose the cardio protective effect of preconditioning 124 and have an increased dependence of heart contractility on Ca 2+ /calmodulin dependent kinase type II and Ca 2+ activated Cl − chan nels 125 . Mutations in CFTR, which induce loss of function of the protein, can therefore affect cardiac function and contribute to cardiac manifestations of cystic fibrosis.…”

Section: Derailment Owing To Genetic Mutationsmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

View full text Add to dashboard Cite

The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

show abstract

Cardiomyocytes with disrupted CFTR function require CaMKII and Ca²⁺‐activated Cl⁻ channel activity to maintain contraction rate

Cited by 42 publications

References 57 publications

Left ventricular and aortic dysfunction in cystic fibrosis mice

Left ventricular and aortic dysfunction in cystic fibrosis mice

Right ventricular dysfunction in adolescents with mild cystic fibrosis

Proteostasis in cardiac health and disease

Contact Info

Product

Resources

About

Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+‐activated Cl− channel activity to maintain contraction rate

Cited by 42 publications

References 57 publications

Left ventricular and aortic dysfunction in cystic fibrosis mice

Left ventricular and aortic dysfunction in cystic fibrosis mice

Right ventricular dysfunction in adolescents with mild cystic fibrosis

Proteostasis in cardiac health and disease

Contact Info

Product

Resources

About

Cardiomyocytes with disrupted CFTR function require CaMKII and Ca²⁺‐activated Cl⁻ channel activity to maintain contraction rate