Dilated Cardiomyopathy Resulting From High-Level Myocardial Expression of Cre-Recombinase

Buerger, Antje; Rozhitskaya, Olga; Sherwood, Megan C.; Dorfman, Adam L.; Bisping, Egbert; Abel, E. Dale; Pu, William T.; Izumo, Seigo; Jay, Patrick Y.

doi:10.1016/j.cardfail.2006.03.002

Cited by 115 publications

(140 citation statements)

References 24 publications

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“…This deficit was age-independent. Others have observed negative effects associated with Cre expression in the developing nervous system and in cardiac tissue; 34,35 however, to our knowledge no reports have indicated a problem in the T29-1 mice. Nevertheless, we do not believe that this problem abrogates our conclusion that the KI/Cre Casp6-expressing mice have an age-dependent spatial memory impairment because when we compare the adult and old KI/Cre, the adult (r15 months) mice show memory retention in the probe test while the old mice show impairment of this function.…”

Section: Discussionmentioning

confidence: 72%

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

et al. 2014

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Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops agedependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. Cell Death and Differentiation (2014) 21, 696-706; doi:10.1038/cdd.2013; published online 10 January 2014The underlying molecular pathway for neuronal degeneration and dysfunction in Alzheimer's disease (AD) remains unknown. Yet, the identification of critical events initiating neuronal degeneration could provide a novel therapeutic approach to stem the progressive dementia of AD. We propose that Caspase-6 (Casp6), a cysteinyl protease of the caspase family, has a critical role in AD neuronal degeneration and cognitive impairment. Casp6 activity is intimately associated with the neuritic plaques (NP), neurofibrillary tangles (NFT), and neuropil threads (NPT) of AD. 1 Casp6 activity is abundant in familial AD 2 and at all stages of sporadic AD. 3 Although no Casp6 activity is present in younger brains, 1 several aged non-cognitively impaired (NCI) brains show significant amounts of Casp6 activity in the entorhinal cortex (ERC), 3 the first area showing NFT pathology in AD according to Braak staging. 4,5 Furthermore, higher levels of Casp6 activity in the ERC and cornu ammonis 1 (CA1) region of NCI brains correlate with lower episodic memory (EP) performance, one of the types of memory also affected early in AD. 6 Active Casp6 induces several parallel degenerative pathways associated with AD neuropathology. First, Casp6 activity disrupts the neuronal cytoskeleton. Casp6 cleaves neuronal microtubule protein alpha-tubulin, microtubuleassociated protein Tau, and actin-regulating post-synaptic density proteins, Spinophilin, Drebrin, and Actinins. 7 In mouse, caspase activity precedes and leads to the formation of NFT-like aggregation. 8 Casp6 activity is involved in axonal degeneration of mouse PNS neurons via amyloid precursor protein (APP) interaction with death receptor 6 9 and in nerve growth factor (NGF)-deprived dorsal root ganglion neurons. 10 Furthermore, Casp6-dependent axonal degeneration i...

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Section: Discussionmentioning

confidence: 72%

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

et al. 2014

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“…In this study, we used a mouse model of DCM (DCM-TG9) and cardiac-specific Tg mice with increased PI3K activity (constitutively active PI3K, caPI3K) or decreased PI3K activity (dominant negative PI3K, dnPI3K) (15,16). DCM-TG9 mice display typical signs of DCM, including ventricular dilatation, impaired systolic function, congestive heart failure, and premature death.…”

Section: Resultsmentioning

confidence: 99%

Protective effects of exercise and phosphoinositide 3-kinase(p110α) signaling in dilated and hypertrophic cardiomyopathy

McMullen

Amirahmadi

Woodcock

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110␣ isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exerciseinduced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110␣) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiacspecific transgenic mice with increased or decreased PI3K(p110␣) activity to the DCM model, and subjected PI3K(p110␣) transgenics to acute pressure overload (ascending aortic constriction). Lifespan, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110␣) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110␣) activity drastically shortened lifespan by Ϸ50%. Increased PI3K(p110␣) activity had a favorable effect on cardiac function and fibrosis in the pressureoverload model and attenuated pathological growth. PI3K(p110␣) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110␥) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110␣) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.heart failure ͉ signal transduction ͉ heart growth ͉ athlete's heart

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“…S6C). Furthermore, prior work by ourselves and others with this specific Cre mouse line has shown no evidence of heart failure (17,(32)(33)(34).…”

Section: Tln2 Deletion Does Not Produce Changes In the Dystrophin-glymentioning

confidence: 88%

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the musclespecific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.T he heart and all of its attendant cells, particularly the contracting cardiac myocytes (CMs), are constantly subjected to high forces. Proper linkage between the cellular cytoskeleton, the cell membrane (termed the sarcolemma in muscle cells), and the extracellular matrix (ECM) is necessary for synchronized force distribution among the cells of the myocardium (1-3). When these linkages are disturbed, forces may be distributed abnormally, cardiac muscle can be injured, and therefore whole-heart function can become abnormal. A number of intracellular proteins and membrane receptors have been found to be crucial for organizing this interactive arrangement between the intracellular CM environment and the surrounding ECM. The integrin family of adhesion receptors are key proteins operative in this response (4). Integrins are a large family of 18 α-subunits and 8 β-subunits, which heterodimerize noncovalently, forming over 24 unique transmembrane receptors on virtually all cells, including CMs. They bind directly to ECM proteins via their proportionally large extracellular domains, and their short cytoplasmic tails assist with organizing a large multiprotein complex that connects integrins to the actin cytoskeleton and may transduce signals to a range of downstream pathways. With these connections, integrins are recognized as key mechanotransducers, converting mechanical perturbations to biochemical signals (...

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Dilated Cardiomyopathy Resulting From High-Level Myocardial Expression of Cre-Recombinase

Cited by 115 publications

References 24 publications

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

Protective effects of exercise and phosphoinositide 3-kinase(p110α) signaling in dilated and hypertrophic cardiomyopathy

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

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