Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of Manganese Superoxide Dismutase via the SIRT1/FoxO3a Pathway

Lai, Lo; Yan, Lin; Gao, Shumin; Hu, Changbing; Ge, Hui; Davidow, Amy L.; Park, Misun; Bravo, Claudio; Iwatsubo, Kousaku; Ishikawa, Yoshihiro; Auwerx, Johan; Sinclair, David A.; Vatner, Stephen F.; Vatner, Dorothy E.

doi:10.1161/circulationaha.112.001212

Cited by 83 publications

(63 citation statements)

References 48 publications

(76 reference statements)

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“…Manganese, essential for many biological systems (e.g., MnSOD, responsible for clearing of high reactive oxygen species) 30 showed also no induction of metabolic activity, but downregulation occurs even at very low concentrations. Manganese will be used as a supplement metal of the iron-based alloys with concentrations <10% (w/w).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo corrosion properties of new iron–manganese alloys designed for cardiovascular applications

et al. 2014

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The principle of biodegradation for the production of temporary implant materials (e.g. stents) plays an important role in the treatment of congenital heart defects. In the last decade several attempts have been made with different alloy materials—mainly based on iron and magnesium. None of the currently available materials in this field have demonstrated satisfying results and have therefore not found entry into broad clinical practice. While magnesium or magnesium alloy systems corrode too fast, the corrosion rate of pure iron‐stents is too slow for cardiovascular applications. In the last years FeMn alloy systems were developed with the idea that galvanic effects, caused by different electrochemical properties of Fe and Mn, would increase the corrosion rate. In vitro tests with alloys containing up to 30% Mn showed promising results in terms of biocompatibility. This study deals with the development of new FeMn alloy systems with lower Mn concentrations (FeMn 0.5 wt %, FeMn 2.7 wt %, FeMn 6.9 wt %) to avoid Mn toxicity. Our results show, that these alloys exhibit good mechanical features as well as suitable in vitro biocompatibility and corrosion properties. In contrast, the evaluation of these alloys in a mouse model led to unexpected results—even after 9 months no significant corrosion was detectable. Preliminary SEM investigations showed that passivation layers (FeMn phosphates) might be the reason for corrosion resistance. If this can be proved in further experiments, strategies to prevent or dissolve those layers need to be developed to expedite the in vivo corrosion of FeMn alloys. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 649–660, 2015.

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Section: Discussionmentioning

confidence: 99%

In vitro and in vivo corrosion properties of new iron–manganese alloys designed for cardiovascular applications

et al. 2014

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“…Therefore, the demonstration of improved exercise performance in the AC5 KO model is particularly germane, as this is also a model for longevity (Yan et al ., 2007), and protects against cardiovascular stress (Okumura et al ., 2003; Lai et al ., 2013), diabetes, and obesity (Ho et al ., 2015). In view of the important link between exercise and longevity, it is surprising that of 20 mouse models we reviewed, only two studied exercise and found it to be increased.…”

Section: Discussionmentioning

confidence: 99%

“…As MnSOD is a downstream target of SIRT1 (Lai et al ., 2013), and FoxO3a is known to regulate MnSOD transcriptionally, it is likely that AC5 regulates expression levels of MnSOD in skeletal muscle also through SIRT1 and FoxO3a. It should be noted that although most studies indicate that antioxidants protect against oxidative stress and thus extend lifespan (Anisimov et al ., 2011; Niu et al ., 2013) and lead to enhanced exercise capacity (Ji et al ., 1998), recently some reports indicated that antioxidants have no beneficial effects on exercise or are even harmful in high concentrations (Selman et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…However, the overwhelming preponderance of data in patients support the concept that exercise improves not only healthy lifespan, but also longevity, as it clearly is protective against cardiovascular disease, diabetes, and obesity, all of which are known to reduce lifespan. As the AC5 KO mice exhibit longevity and protection against diabetes, obesity, and cardiovascular disease (Yan et al ., 2007, 2014; Lai et al ., 2013; Ho et al ., 2015) along with enhanced exercise performance demonstrated in the current investigation, this model replicates the human paradigm of healthful aging. Conversely, enhanced β adrenergic signaling results in diminished lifespan, not only in transgenic animal models, for example, overexpression of Gsα (Iwase et al ., 1996, 1997), but also in human aging studies with increased β2 adrenergic receptor genotype, where longevity is diminished (Zhao et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Generation of AC5 shRNA adenovirus (Ad‐AC5 shRNA) was described previously (Lai et al ., 2013). Ad‐AC5 shRNA was added to L6 rat skeletal muscle cells with 80% confluence, following 72–96 h of incubation.…”

Section: Methodsmentioning

confidence: 99%

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Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

et al. 2015

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SummaryThe most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β‐AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac‐ and skeletal muscle‐specific AC5 KO's, where exercise performance was no longer improved by the cardiac‐specific AC5 KO, but was by the skeletal muscle‐specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti‐oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy‐3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.

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Interatrial differences of basal molecular set‐up and changes in tachycardia‐induced heart failure–a proteomic profiling study

Dietl¹,

Winkel

Deutzmann³

et al. 2014

European J of Heart Fail

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AimsLeft and right atria show compelling differences regarding organogenesis and specific clinical diseases. In congestive heart failure (CHF), remodelling of the atria occurs leading to increased arrhythmogenic susceptibility and deterioration of clinical symptoms. We aimed to assess the basal left and right atrial molecular set-up and different chamber-specific atrial changes in heart failure. Methods and resultsWe combined an animal model of rapid ventricular pacing induced heart failure in the rabbit and a gel-based proteomic screening of left and right atrial specimen. A gene ontology over-representation analysis was performed for biological function. Ultrastructural adaptations were evaluated using transmission electron microscopy. Comparing left and right atria of healthy control animals (CTRL), 39 proteins displayed significant expression differences involving various biological functions. Upon further statistical analyses, four pathways of energy metabolism were confirmed to be significantly over-represented beneath the other biological processes. Rapid ventricular pacing induced severe left ventricular systolic dysfunction, symptomatic heart failure and a macroscopic atrial remodelling. In CHF versus CTRL, metabolic and antioxidative enzymes were differentially expressed and showed chamber-specific bidirectional alterations. Transmission electron microscopy visualized a remarkable and again chamber-specific ultrastructural disturbance of mitochondrial morphology.

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Type 5 Adenylyl Cyclase Increases Oxidative Stress by Transcriptional Regulation of Manganese Superoxide Dismutase via the SIRT1/FoxO3a Pathway

Cited by 83 publications

References 48 publications

In vitro and in vivo corrosion properties of new iron–manganese alloys designed for cardiovascular applications

In vitro and in vivo corrosion properties of new iron–manganese alloys designed for cardiovascular applications

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

Interatrial differences of basal molecular set‐up and changes in tachycardia‐induced heart failure–a proteomic profiling study

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