Cardiac-specific overexpression of E40K active Akt prevents pressure overload-induced heart failure in mice by increasing angiogenesis and reducing apoptosis

Ceci, Marcello; Gallo, Paolo; Santonastasi, Marco; Grimaldi, Séréna; Latronico, Michael V.G.; Pitisci, A; Missol-Kolka, Ewa; Scimia, Maria Cecilia; Catalucci, Daniele; Hilfiker‐Kleiner, Denise; Condorelli, Gianluigi

doi:10.1038/sj.cdd.4402095

Cited by 43 publications

(40 citation statements)

References 17 publications

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“…Akt1, a well-characterized downstream regulator of PI3K, has also been shown to provide protection against pressure overload-induced dysfunction and increase angiogenesis in a paracrine manner. 42,44,45 However, whereas chronic activation of PI3K has no reported adverse effects, 17,20 the impact of Akt seems to be dependent on subcellular localization and the degree of Akt activation and cardiac growth. 45 A recognized challenge in the cardiac field is the similarities between signaling pathways that drive tumorigenesis and those that regulate protection in the heart.…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-Kinase p110α Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction

Weeks

Gao

et al. 2012

Circ: Heart Failure

116

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Background— Numerous molecular and biochemical changes have been linked with the cardioprotective effects of exercise, including increases in antioxidant enzymes, heat shock proteins, and regulators of cardiac myocyte proliferation. However, a master regulator of exercise-induced protection has yet to be identified. Here, we assess whether phosphoinositide 3-kinase (PI3K) p110α is essential for mediating exercise-induced cardioprotection, and if so, whether its activation independent of exercise can restore function of the failing heart. Methods and Results— Cardiac-specific transgenic (Tg) mice with elevated or reduced PI3K(p110α) activity (constitutively active PI3K [caPI3K] and dominant negative PI3K, respectively) and non-Tg controls were subjected to 4 weeks of exercise training followed by 1 week of pressure overload (aortic-banding) to induce pathological remodeling. Aortic-banding in untrained non-Tg controls led to pathological cardiac hypertrophy, depressed systolic function, and lung congestion. This phenotype was attenuated in non-Tg controls that had undergone exercise before aortic-banding. Banded caPI3K mice were protected from pathological remodeling independent of exercise status, whereas exercise provided no protection in banded dominant negative PI3K mice, suggesting that PI3K is necessary for exercise-induced cardioprotection. Tg overexpression of heat shock protein 70 could not rescue the phenotype of banded dominant negative PI3K mice, and deletion of heat shock protein 70 from banded caPI3K mice had no effect. Next, we used a gene therapy approach (recombinant adeno-associated viral vector 6) to deliver caPI3K expression cassettes to hearts of mice with established cardiac dysfunction caused by aortic-banding. Mice treated with recombinant adeno-associated viral 6-caPI3K vectors had improved heart function after 10 weeks. Conclusions— PI3K(p110α) is essential for exercise-induced cardioprotection and delivery of caPI3K vector can improve function of the failing heart.

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Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-Kinase p110α Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction

Weeks

Gao

et al. 2012

Circ: Heart Failure

116

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“…Moreover, overexpression of active Akt was demonstrated to blunt pressure overload-induced HF development in mice (17), whereas deletion of Akt worsened it (18). Thus, reduced activity of MTOR has an important role in the negative modulation of cardiac function occurring with disease.…”

Section: Introductionmentioning

confidence: 99%

MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice

Zhang¹,

Contu²,

Latronico³

et al. 2010

J. Clin. Invest.

300

185

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Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully elucidated. Here, we show that ablation of Mtor in the adult mouse myocardium results in a fatal, dilated cardiomyopathy that is characterized by apoptosis, autophagy, altered mitochondrial structure, and accumulation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). 4E-BP1 is an MTOR-containing multiprotein complex-1 (MTORC1) substrate that inhibits translation initiation. When subjected to pressure overload, Mtor-ablated mice demonstrated an impaired hypertrophic response and accelerated HF progression. When the gene encoding 4E-BP1 was ablated together with Mtor, marked improvements were observed in apoptosis, heart function, and survival. Our results demonstrate a role for the MTORC1 signaling network in the myocardial response to stress. In particular, they highlight the role of 4E-BP1 in regulating cardiomyocyte viability and in HF. Because the effects of reduced MTOR activity were mediated through increased 4E-BP1 inhibitory activity, blunting this mechanism may represent a novel therapeutic strategy for improving cardiac function in clinical HF.

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“…AKT is considered to exert a cardioprotective role; and several evidences support that its activation reduces the apoptosis of cardiomyocytes under ischemia-reperfusion conditions [37], oxidative stress [40] and heart failure induced by pressure overload in mice [62]. AKT substrates exert a decisive influence on cellular functions in myocardium that includes growth, survival, proliferation and also glucose uptake, gene expression and cell to cell communication through autocrine and paracrine factors [18].…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

“…1 and 2). The loss of cardiomyocytes has dramatic consequences at cardiac level: the dysregulation of death and survival pathways leading to cardiac myocyte apoptosis in failing hearts is a causal component not only in acute ischemic injury but also in more chronic heart failure states [60,61] and contributes to cardiac remodelling and contractile failure [62][63][64]. Apoptosis plays in fact a crucial role in the development of heart failure [65], and previous studies have reported an apoptosis rate ranging from 0.12% to 0.70% in human failing hearts [65].…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 99%

The Adipokine Chemerin Induces Apoptosis in Cardiomyocytes

Rodríguez-Penas¹,

Feijóo‐Bandín²,

García-Rúa³

et al. 2015

Cell Physiol Biochem

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Background: The adipokine chemerin has been associated with cardiovascular disease. We investigated the effects of chemerin on viability and intracellular signalling in murine cardiomyocytes, and the effects of insulin and TNF-α on cardiomyocyte chemerin production. Methods: Hoechst dye vital staining and cell cycle analysis were used to analyse the viability of murine cardiac cells in culture. Western blot was used to explore the phosphorylation of AKT and caspase-9 activity in neonatal rat cardiomyocytes and HL-1 cells. Finally, RT-qPCR, ELISA and western blot were performed to examine chemerin and CMKLR1 expression after insulin and TNF-α treatment in cardiac cells. Results: Chemerin treatment increased apoptosis, reduced phosphorylation of AKT at Thr308 and increased caspase-9 activity in murine cardiomyocytes. Insulin treatment lowered chemerin and CMKLR1 mRNA and protein levels, and the amount of chemerin in the cell media, while TNF-α treatment increased chemerin mRNA and protein levels but decreased expression of the CMKLR1 gene. Conclusion: Chemerin induces apoptosis, reduces AKT phosphorylation and increases the cleavage of caspase-9 in murine cardiomyocytes. The expression of chemerin is regulated by important metabolic (insulin) and inflammatory (TNF-α) mediators at cardiac level. Our results suggest that chemerin could play a role in the physiopathology of cardiac diseases.

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Cardiac-specific overexpression of E40K active Akt prevents pressure overload-induced heart failure in mice by increasing angiogenesis and reducing apoptosis

Cited by 43 publications

References 17 publications

Phosphoinositide 3-Kinase p110α Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction

Phosphoinositide 3-Kinase p110α Is a Master Regulator of Exercise-Induced Cardioprotection and PI3K Gene Therapy Rescues Cardiac Dysfunction

MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice

The Adipokine Chemerin Induces Apoptosis in Cardiomyocytes

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