Inhibition of Adenylyl Cyclase Type 5 Increases Longevity and Healthful Aging through Oxidative Stress Protection

Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against diabetes, obesity, and the cardiomyopathy induced by aging, diabetes, and cardiac stress and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection. For example, chronic beta adrenergic receptor stimulation induced cardiomyopathy was rescued by AC5 KO. Conversely, in AC5 transgenic (Tg) mice, where AC5 is overexpressed in the heart, the cardiomyopathy was exacerbated and was rescued by enhancing oxidative stress resistance. Thus, the AC5 KO model, which resists oxidative stress, is uniquely designed for clinical translation, since it not only increases longevity and exercise, but also protects against diabetes, obesity, and cardiomyopathy. Importantly, inhibition of AC5’s action to prolong longevity and enhance healthful aging, as well as its mechanism through resistance to oxidative stress, is unique among all of the nine AC isoforms.

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Caveolin-1 promotes radioresistance in rhabdomyosarcoma through increased oxidative stress protection and DNA repair

Cancer Letters ◽

10.1016/j.canlet.2021.02.005 ◽

2021 ◽

Vol 505 ◽

pp. 1-12

Author(s):

Silvia Codenotti ◽

Francesco Marampon ◽

Luca Triggiani ◽

Marco Lorenzo Bonù ◽

Stefano Maria Magrini ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Repair ◽

Caveolin 1 ◽

Stress Protection ◽

Oxidative Stress Protection

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Engineered EVs for Oxidative Stress Protection

Pharmaceuticals ◽

10.3390/ph14080703 ◽

2021 ◽

Vol 14 (8) ◽

pp. 703

Author(s):

Anna Maria Tolomeo ◽

Santina Quarta ◽

Alessandra Biasiolo ◽

Mariagrazia Ruvoletto ◽

Michela Pozzobon ◽

...

Keyword(s):

Oxidative Stress ◽

Extracellular Vesicles ◽

Transgene Expression ◽

Hepatoma Cell ◽

Serine Protease Inhibitor ◽

Protein Product ◽

Hepatoma Cell Line ◽

Cytoprotective Activity ◽

Stress Protection ◽

Oxidative Stress Protection

Extracellular vesicles (EVs) are increasingly studied as vectors for drug delivery because they can transfer a variety of molecules across biological barriers. SerpinB3 is a serine protease inhibitor that has shown a protective anti-apoptotic function in a variety of stressful conditions. The aim of this study was to evaluate protection from oxidative stress-induced damage, using extracellular vesicles that overexpress SerpinB3 (EVs-SB3) in order to enhance the effect of extracellular vesicles on cellular homeostasis. EVs-SB3s were obtained from HepG2 cells engineered to overexpress SerpinB3 and they revealed significant proteomic changes, mostly characterized by a reduced expression of other proteins compared with EVs from non-engineered cells. These EV preparations showed a significantly higher protection from H2O2 induced oxidative stress in both the hepatoma cell line and in primary cardiomyocytes, compared to cells treated with naïve EVs or SerpinB3 alone, used at the same concentration. In conclusion, the induction of SerpinB3 transgene expression results in the secretion of EVs enriched with the protein product that exhibits enhanced cytoprotective activity, compared with naïve EVs or the nude SerpinB3 protein.

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TGF-beta-induced early gene-1 overexpression promotes oxidative stress protection and actin cytoskeleton rearrangement in human skin fibroblasts

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2016.02.009 ◽

2016 ◽

Vol 1860 (6) ◽

pp. 1071-1078 ◽

Cited By ~ 10

Author(s):

Chloe Leduc ◽

Lauren Sobilo ◽

Hechmi Toumi ◽

Philippe Mondon ◽

Eric Lespessailles ◽

...

Keyword(s):

Oxidative Stress ◽

Actin Cytoskeleton ◽

Human Skin ◽

Skin Fibroblasts ◽

Early Gene ◽

Tgf Beta ◽

Human Skin Fibroblasts ◽

Stress Protection ◽

Oxidative Stress Protection ◽

Cytoskeleton Rearrangement

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Adenylyl cyclase type 5 protein expression during cardiac development and stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00050.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. H1776-H1782 ◽

Cited By ~ 36

Author(s):

Che-Lin Hu ◽

Rachna Chandra ◽

Hui Ge ◽

Jayashree Pain ◽

Lin Yan ◽

...

Keyword(s):

Adenylyl Cyclase ◽

Adrenergic Receptor ◽

Ventricular Hypertrophy ◽

Cardiac Development ◽

Mammalian Species ◽

Pressure Overload ◽

Left Ventricular ◽

Receptor Stimulation ◽

Specific Antibodies ◽

The Brain

Adenylyl cyclase (AC) types 5 and 6 (AC5 and AC6) are the two major AC isoforms expressed in the mammalian heart that mediate signals from β-adrenergic receptor stimulation. Because of the unavailability of isoform-specific antibodies, it is difficult to ascertain the expression levels of AC5 protein in the heart. Here we demonstrated the successful generation of an AC5 isoform-specific mouse monoclonal antibody and studied the expression of AC5 protein during cardiac development in different mammalian species. The specificity of the antibody was confirmed using heart and brain tissues from AC5 knockout mice and from transgenic mice overexpressing AC5. In mice, the AC5 protein was highest in the brain but was also detectable in all organs studied, including the heart, brain, lung, liver, stomach, kidney, skeletal muscle, and vascular tissues. Western blot analysis showed that AC5 was most abundant in the neonatal heart and declined to basal levels in the adult heart. AC5 protein increased in the heart with pressure-overload left ventricular hypertrophy. Thus this new AC5 antibody demonstrated that this AC isoform behaves similarly to fetal type genes, such as atrial natriuretic peptide; i.e., it declines with development and increases with pressure-overload hypertrophy.

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Reduced Oxidative Stress as a Mechanism for Increased Longevity, Exercise and Heart Failure Protection with Adenylyl Cyclase Type 5 Inhibition

Biochemistry of Oxidative Stress ◽

10.1007/978-3-319-45865-6_10 ◽

2016 ◽

pp. 147-161

Author(s):

Stephen F. Vatner ◽

Jie Zhang ◽

Dorothy E. Vatner

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Adenylyl Cyclase ◽

Adenylyl Cyclase Type 5

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Abstract 5501: Reduced Coronary Reserve as a Mechanism in Beta-Adrenergic Receptor Mediated Cardiomyopathy and its Rescue by Adenylyl Cyclase Type 5 Knockout

Circulation ◽

10.1161/circ.118.suppl_18.s_562-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Shumin Gao ◽

Lin Yan ◽

Chull Hong ◽

Xin Zhao ◽

Li Chen ◽

...

Keyword(s):

Adenylyl Cyclase ◽

Mouse Models ◽

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Potential Mechanism ◽

Wild Type ◽

Coronary Reserve ◽

Small Heart ◽

Cardinal Feature ◽

Adenylyl Cyclase Type 5

Reduced coronary reserve (CR) is a cardinal feature of human cardiomyopathy, but it has not been studied extensively in mouse models of cardiomyopathy, potentially because of difficulties inherent to measuring CR in such a small heart. The first goal of this study was to determine if reduced CR is a potential mechanism involved in a transgenic (Tg) mouse model of cardiomyopathy, induced by cardiac overexpression of beta 2 -adrenergic receptors (beta 2 -AR Tg). Older beta 2 -AR Tg mice (16–17 months, n=7) developed cardiomyopathy, as reflected by decreased LV ejection fraction (LVEF, 50±7%), and increased fibrosis (5.2±0.4%) and apoptosis (3.8±0.6%). CR was obtained by measuring LV coronary blood flow at baseline and with adenosine (160 microg/kg/min) induced hyperemia using high resolution ultrasound (Vevo 770). CR was significantly decreased in beta 2 -AR Tg (1.8±0.2) compared with wild type (WT) (3.0±0.3, n=6). The next goal was to determine if the rescue of the beta 2 -AR Tg cardiomyopathy resulted in a rescue of reduced CR. Since adenylyl cyclase type 5 knockout (AC5 KO) mice are protected against catecholamine stress and the development of heart failure (HF), and exhibit enhanced CR (3.7±0.4, n=5), we hypothesized that mating these mice with beta 2 -AR Tg might rescue the cardiomyopathy. Older (16–17 months, n=4) bigenic mice (beta 2 -AR Tg x AC5 KO) demonstrated a rescue of cardiomyopathy, as reflected by normalized LVEF (71±1%) and levels of apoptosis (0.11±0.01%) and fibrosis (1.09±0.33%), similar to WT. In these mice, CR was also normalized (3.4±0.6). Reduced CR in beta 2 -AR Tg cardiomyopathy is similar to that observed in large mammalian models, and in patients with cardiomyopathy. Thus, this mechanism is important to consider in mouse models of cardiomyopathy, in general, and also in particular for the mechanism of the rescue of the beta 2 -AR Tg cardiomyopathy by AC5 KO.

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