CNPase, a 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase, as a Therapeutic Target to Attenuate Cardiac Hypertrophy by Enhancing Mitochondrial Energy Production

Abstract

Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2′-3′-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2′,3′-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity.

The protective effect of fluoxetine on hippocampal oligodendrocytes in AD mice: a potential mechanism involving S100B

“…2′,3′-cAMP is a mitochondrial toxin, and 2-AMP is a neuroprotective agent CNPase can protect oligodendrocytes and axons from injury by reducing the levels of 2′,3′-cAMP and increasing the levels of 2-AMP [52]. A previous study also showed that CNPase can protect mitochondria from AngII-induced metabolic stress [53]. Therefore, in this study, we analysed the mitochondria of oligodendrocytes.…”

Identification of candidate biomarkers and pathways associated with multiple sclerosis using bioinformatics and next generation sequencing data analysis

“…The expression of CCL18 [109], SLAMF7 [110], GPR174 [111], CCR4 [112], POU4F2 [113]. CCR2 [114], IL2RB [115], CCL4 [116], CCL24 [117], FASLG (Fas ligand) [118], CD24 [119], TDGF1 [120], CD28 [121], IL7R [122], CYP11B1 [123], CCL5 [124], CCL3 [125], LTF (lactotransferrin) [126], GPNMB (glycoprotein nmb) [127], CD209 [128], IL2RG [129], CHIT1 [130], TAB2 [131], CD163 [132], ALOX15B [133], NMRK2 [134], HGF (hepatocyte growth factor) [135], TRPM8 [136], DIO3 [137], SIGLEC1 [138], TTR (transthyretin) [139], IL24 [140], F13A1 [141], IL9 [142], VEGFA (vascular endothelial growth factor A) [143], RASAL1 [144], ADM (adrenomedullin) [145], ANGPTL4 [146], CHI3L1 [147], LDB3 [148], CNP (2’,3’-cyclic nucleotide 3’ phosphodiesterase) [149], HES6 [150], CMTM5 [151], PLXNB3 [152], KLK8 [153], CDKN1C [154], INSIG1 [155], GREM1 [156], ATF3 [157], HK2 [158], MCAM (melanoma cell adhesion molecule) [159], SEMA4D [160], GLUL (glutamate-ammonia ligase) [161], S1PR5 [162], FN3K [163], MEIS1 [164], ADAMTS4 [165], BIN1 [166], BMP2 [167], LMNA (lamin A/C) [168], ERBB3 [169], DLL1 [170], THBS2 [171], GADD45B [172], MYH6 [173]. PNPLA3 [174], ACTN2 [175], MMP15 [176], SVEP1 [177], CPB2 [178], DYSF (dysferlin) [179], ADAMTSL2 [180], NINJ2 [181], LRP2 [106], PHLDA3 […”

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species

“…Another approach to modeling is to simulate the symptoms of the target disease through mutations in genes with known function. Individuals and lines have been created that exhibit analogs of human somatic diseases such as cataract [ 49 , 50 ], myopia [ 51 ], exfoliative syndrome [ 52 ], retinal dysfunction [ 53 , 54 ], congenital heart defect [ 55 ], cardiac hypertrophy [ 56 ], dilated cardiomyopathy [ 57 ], arrhythmia [ 58 ], autoinflammatory syndrome [ 59 ], metabolic syndrome [ 60 ], diabetes and obesity [ 61 ], tuberculosis [ 62 ], thrombocytopenia [ 63 ], pediatric intestinal pseudoobstruction [ 64 ], pediatric cirrhosis [ 65 ], congenital hypothyroidism [ 66 ], fatty or alcoholic hepatosis [ 67 ], and scoliosis [ 68 , 69 ]. Genome editing has been used to model human tumors such as liver cancer [ 70 ], paraganglioma [ 71 ], skin melanoma [ 72 ], and epithelioid sarcoma [ 73 ].…”