Pierluigi Carullo

@article{kallikourdis_t_2017,

title = {T cell costimulation blockade blunts pressure overload-induced heart failure},

author = {Marinos Kallikourdis and Elisa Martini and Pierluigi Carullo and Claudia Sardi and Giuliana Roselli and Carolina M Greco and Debora Vignali and Federica Riva and Anne Marie {Ormbostad Berre} and Tomas O St{ø}len and Andrea Fumero and Giuseppe Faggian and Elisa {Di Pasquale} and Leonardo Elia and Cristiano Rumio and Daniele Catalucci and Roberto Papait and Gianluigi Condorelli},

doi = {10.1038/ncomms14680},

issn = {2041-1723},

year  = {2017},

date = {2017-03-01},

journal = {Nature Communications},

volume = {8},

pages = {14680},

abstract = {Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{greco_dna_2016,

title = {DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy},

author = {Carolina M Greco and Paolo Kunderfranco and Marcello Rubino and Veronica Larcher and Pierluigi Carullo and Achille Anselmo and Kerstin Kurz and Thomas Carell and Andrea Angius and Michael V G Latronico and Roberto Papait and Gianluigi Condorelli},

doi = {10.1038/ncomms12418},

issn = {2041-1723},

year  = {2016},

date = {2016-08-01},

journal = {Nature Communications},

volume = {7},

pages = {12418},

abstract = {Methylation at 5-cytosine (5-mC) is a fundamental epigenetic DNA modification associated recently with cardiac disease. In contrast, the role of 5-hydroxymethylcytosine (5-hmC)-5-mC's oxidation product-in cardiac biology and disease is unknown. Here we assess the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks during heart development and failure. DNA hydroxymethylation marks the body of highly expressed genes as well as distal regulatory regions with enhanced activity. Moreover, pathological hypertrophy is characterized by a shift towards a neonatal 5-hmC distribution pattern. We also show that the ten-eleven translocation 2 (TET2) enzyme regulates the expression of key cardiac genes, such as Myh7, through 5-hmC deposition on the gene body and at enhancers. Thus, we provide a genome-wide analysis of 5-hmC in the cardiomyocyte and suggest a role for this epigenetic modification in heart development and disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{rusconi_peptidomimetic_2016,

title = {Peptidomimetic Targeting of Cavβ2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function},

author = {Francesca Rusconi and Paola Ceriotti and Michele Miragoli and Pierluigi Carullo and Nicol{ò} Salvarani and Marcella Rocchetti and Elisa {Di Pasquale} and Stefano Rossi and Maddalena Tessari and Silvia Caprari and Magali Cazade and Paolo Kunderfranco and Jean Chemin and Marie-Louise Bang and Fabio Polticelli and Antonio Zaza and Giuseppe Faggian and Gianluigi Condorelli and Daniele Catalucci},

doi = {10.1161/CIRCULATIONAHA.116.021347},

issn = {1524-4539},

year  = {2016},

date = {2016-08-01},

journal = {Circulation},

volume = {134},

number = {7},

pages = {534--546},

abstract = {BACKGROUND: L-type calcium channels (LTCCs) play important roles in regulating cardiomyocyte physiology, which is governed by appropriate LTCC trafficking to and density at the cell surface. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in conditions of cardiac physiology and disease. 

METHODS: Yeast 2-hybrid screenings, biochemical and molecular evaluations, protein interaction assays, fluorescence microscopy, structural molecular modeling, and functional studies were used to investigate the molecular mechanisms through which the LTCC Cavβ2 chaperone regulates channel density at the plasma membrane. 

RESULTS: On the basis of our previous results, we found a direct linear correlation between the total amount of the LTCC pore-forming Cavα1.2 and the Akt-dependent phosphorylation status of Cavβ2 both in a mouse model of diabetic cardiac disease and in 6 diabetic and 7 nondiabetic cardiomyopathy patients with aortic stenosis undergoing aortic valve replacement. Mechanistically, we demonstrate that a conformational change in Cavβ2 triggered by Akt phosphorylation increases LTCC density at the cardiac plasma membrane, and thus the inward calcium current, through a complex pathway involving reduction of Cavα1.2 retrograde trafficking and protein degradation through the prevention of dynamin-mediated LTCC endocytosis; promotion of Cavα1.2 anterograde trafficking by blocking Kir/Gem-dependent sequestration of Cavβ2, thus facilitating the chaperoning of Cavα1.2; and promotion of Cavα1.2 transcription by the prevention of Kir/Gem-mediated shuttling of Cavβ2 to the nucleus, where it limits the transcription of Cavα1.2 through recruitment of the heterochromatin protein 1γ epigenetic repressor to the Cacna1c promoter. On the basis of this mechanism, we developed a novel mimetic peptide that, through targeting of Cavβ2, corrects LTCC life-cycle alterations, facilitating the proper function of cardiac cells. Delivery of mimetic peptide into a mouse model of diabetic cardiac disease associated with LTCC abnormalities restored impaired calcium balance and recovered cardiac function. 

CONCLUSIONS: We have uncovered novel mechanisms modulating LTCC trafficking and life cycle and provide proof of concept for the use of Cavβ2 mimetic peptide as a novel therapeutic tool for the improvement of cardiac conditions correlated with alterations in LTCC levels and function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{castaldi_microrna-133_2014,

title = {MicroRNA-133 modulates the β1-adrenergic receptor transduction cascade},

author = {Alessandra Castaldi and Tania Zaglia and Vittoria {Di Mauro} and Pierluigi Carullo and Giacomo Viggiani and Giulia Borile and Barbara {Di Stefano} and Gabriele Giacomo Schiattarella and Maria Giovanna Gualazzi and Leonardo Elia and Giuliano Giuseppe Stirparo and Maria Luisa Colorito and Gianluigi Pironti and Paolo Kunderfranco and Giovanni Esposito and Marie-Louise Bang and Marco Mongillo and Gianluigi Condorelli and Daniele Catalucci},

doi = {10.1161/CIRCRESAHA.115.303252},

issn = {1524-4571},

year  = {2014},

date = {2014-07-01},

journal = {Circulation Research},

volume = {115},

number = {2},

pages = {273--283},

abstract = {RATIONALE: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of β-adrenergic receptors leads to impaired cardiac function, and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability. 

OBJECTIVE: To determine whether miR-133 affects β-adrenergic receptor signaling during progression to heart failure. 

METHODS AND RESULTS: Based on bioinformatic analysis, β1-adrenergic receptor (β1AR) and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective β1AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice. 

CONCLUSIONS: miR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{zaglia_atrogin-1_2014,

title = {Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy},

author = {Tania Zaglia and Giulia Milan and Aaron Ruhs and Mauro Franzoso and Enrico Bertaggia and Nicola Pianca and Andrea Carpi and Pierluigi Carullo and Paola Pesce and David Sacerdoti and Cristiano Sarais and Daniele Catalucci and Marcus Kr{ü}ger and Marco Mongillo and Marco Sandri},

doi = {10.1172/JCI66339},

issn = {1558-8238},

year  = {2014},

date = {2014-06-01},

journal = {The Journal of Clinical Investigation},

volume = {124},

number = {6},

pages = {2410--2424},

abstract = {Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The muscle-specific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin-1-mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}