Heart failure (HF) is associated with complicated molecular remodelling within cardiomyocytes; however, the mechanisms underlying this process remain unclear. Here we show that sorting nexin-13 (SNX13), a member of both the sorting nexin and the regulator of G protein signalling (RGS) protein families, is a potent mediator of HF. Decreased levels of SNX13 are observed in failing hearts of humans and of experimental animals. SNX13-deficient zebrafish recapitulate HF with striking cardiomyocyte apoptosis. Mechanistically, a reduction in SNX13 expression facilitates the degradative sorting of apoptosis repressor with caspase recruitment domain (ARC), which is a multifunctional inhibitor of apoptosis. Consequently, the apoptotic pathway is activated, resulting in the loss of cardiac cells and the dampening of cardiac function. The N-terminal PXA structure of SNX13 is responsible for mediating the endosomal trafficking of ARC. Thus, this study reveals that SNX13 profoundly affects cardiac performance through the SNX13-PXA-ARC-caspase signalling pathway.

Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy.

Ischaemic cardiac arrhythmias cause a large proportion of sudden cardiac deaths worldwide. The ischaemic arrhythmogenesis is primarily because of the dysfunction and adverse remodelling of sarcolemma ion channels. However, the potential regulators of sarcolemma ion channel turnover and function in ischaemic cardiac arrhythmias remains unknown. Our previous studies indicate that dynamin‐2 ( DNM 2), a cardiac membrane‐remodelling GTP ase, modulates ion channels membrane trafficking in the cardiomyocytes. Here, we have found that DNM 2 plays an important role in acute ischaemic arrhythmias. In rat ventricular tissues and primary cardiomyocytes subjected to acute ischaemic stress, the DNM 2 protein and transcription levels were markedly down‐regulated. This DNM 2 reduction was coupled with severe ventricular arrhythmias. Moreover, we identified that the down‐regulation of DNM 2 within cardiomyocytes increases the action potential amplitude and prolongs the re‐polarization duration by depressing the retrograde trafficking of Nav1.5 and Kir2.1 channels. These effects are likely to account for the DNM 2 defect‐induced arrhythmogenic potentials. These results suggest that DNM 2, with its multi‐ion channel targeting properties, could be a promising target for novel antiarrhythmic therapies.

BackgroundHeart failure (HF) is approaching an epidemic proportion and has become one of the leading causes of death. It imposes a great burden on the healthcare system and society. Remodeling of cardiomyocyte membranes has a profound role in the pathogenesis of HF. However, whether dynamin (DNM), a membrane-remodeling GTPase, is associated with HF remains unclear.Methods and resultsHere, we identified that DNM2 is necessary for the maintenance of cardiac function. Endogenous DNM2 protein levels were gradually decreased in parallel with the progression of HF in different experimental animal models. Decreased DNM2 level was also observed in the end-stage failing human heart. DNM2-deficient zebrafish exhibited signs of notable cardiac apoptosis and eventually developed severe HF. Mechanistic study showed that DNM2 downregulation caused cardiomyocyte sarcoplasmic reticulum Ca2+ overload and subsequent mitochondria-dependent apoptosis. These events were preceded by enhanced membrane translocation of the L-type Ca2+ channel due to DNM2 deficiency-mediated membrane trafficking dysfunction. Furthermore, prevention of cardiomyocyte Ca2+-mishandling largely ameliorated the DNM2 deficiency-associated cardiomyocyte apoptosis and HF.ConclusionsDNM2 mediates HF by modulating Ca2+-dependent apoptotic death of cardiomyocyte. The finding may shed light on the new strategy of HF treatment.

Cyclic adenosine 3',5'-monophosphate (cAMP), which is synthesized by adenylyl cyclase (AC) and degraded by phosphodiesterase (POE), plays crucial roles in the regulation of multiple cellular functions and physiological processes. Prolyl hydroxylase domain (PHD) proteins, which belong to a family of dioxygenases that function as oxygen sensors-through their hydroxylation activity, have been implicated in multiple signaling pathways. Here, we aimed to determine whether PHD played a role in regulating intracellular cAMP level in cardiomyocytes. Through the overexpression/knockdown of the PHD gene and the measurement of the cAMP content, we found that PHD2, but not PHD1 or PHD3, acts as a regulator of intracellular cAMP. In neonatal rat cardiomyocytes and H9c2 cells, the overexpression of PHD2 increased the intracellular cAMP level, whereas the PHD2 knockdown reduced it. There was no alteration in the AC expression or activity in cells that overexpressed or downregulated PHD2. The overexpression of PHD2 decreased both the protein expression and the activity of phosphodiesterase 4D (PDE4D), whereas the PHD2 knockdown increased the PDE4D expression and activity. Co-immunoprecipitation experiments revealed a direct binding between PHD2 and PDE4D and liquid chromatography-tandem mass spectrometry analyses identified the specific hydroxylation sites on PDE4D. In conclusion, PHD2 may directly interact with PDE4D to function as a novel regulator of the intracellular cAMP levels in cardiomyocytes. (C) 2012 Elsevier Inc. All rights reserved.