Receptor-interacting protein 140 overexpression impairs cardiac mitochondrial function and accelerates the transition to heart failure in chronically infarcted rats.

Heart failure (HF) is associated with myocardial energy metabolic abnormality. Receptor-interacting protein 140 (RIP140) is an important transcriptional cofactor for maintaining energy balance in high-oxygen consumption tissues. However, the role of RIP140 in the pathologic processes of HF remains to be elucidated. In this study, we investigated the role of RIP140 in mitochondrial and cardiac functions in rodent hearts under myocardial infarction (MI) stress. MI was created by a permanent ligation of left anterior descending coronary artery and exogenous expression of RIP140 by adenovirus (Ad) vector delivery. Four weeks after MI or Ad-RIP140 treatment, cardiac function was assessed by echocardiographic and hemodynamics analyses, and the mitochondrial function was determined by mitochondrial genes expression, biogenesis, and respiration rates. In Ad-RIP140 or MI group, a subset of metabolic genes changed, accompanied with slight reductions in mitochondrial biogenesis and respiration rates but no change in adenosine triphosphate (ATP) content. Cardiac malfunction was compensated. However, under MI stress, rats overexpressing RIP140 exhibited greater repressions in mitochondrial genes, state 3 respiration rates, respiration control ratio, and ATP content and had further deteriorated cardiac malfunction. In conclusion, RIP140 overexpression leads to comparable cardiac function as resulted from MI, but RIP140 aggravates metabolic repression, mitochondrial malfunction, and further accelerates the transition to HF in response to MI stress.

RIP140 triggers foam-cell formation by repressing ABCA1/G1 expression and cholesterol efflux via liver X receptor.

Receptor-interacting protein 140 (RIP140) is a multifunctional coregulator of lipid metabolism and inflammation. However, the potential role of RIP140 in atherosclerosis remains unknown. The present study investigated the impact of RIP140 on foam cell formation, a critical step in pathogenesis of atherosclerosis. The expression of RIP140 was increased in foam cells. RIP140 overexpression resulted in decreased cholesterol efflux in macrophages and their concomitant differentiation into foam cells. Moreover, RIP140 negatively regulated the macrophage expression of ATP-binding cassette transporters A1 and G1 (ABCA1/G1), by suppressing the expression and activity of liver X receptor (LXR). These findings shed light onto the contribution of RIP140 to the development and progression of atherosclerosis, and suggest a novel therapeutic target for the treatment of atherosclerosis.

SLC41A1 knockdown inhibits angiotensin II-induced cardiac fibrosis by preventing Mg(2+) efflux and Ca(2+) signaling in cardiac fibroblasts.

Na(+)/Mg(2+) exchanger plays an important role in cardiovascular system, but the molecular mechanisms still largely remain unknown. The Solute Carrier family 41A1 (SLC41A1), a novel Mg(2+) transporter, recently was found to function as Na(+)/Mg(2+) exchanger, which mainly regulates the intracellular Mg(2+) ([Mg(2+)]i) homeostasis. Our present studies were designed to investigate whether SLC41A1 impacts on the fibrogenesis of cardiac fibroblasts under Ang II stimulation. Our results showed that quinidine, a prototypical inhibitor of Na(+)/Mg(2+) exchanger, inhibited Ang II-induced cardiac fibrosis via attenuating the overexpression of vital biomarkers of fibrosis, including connective tissue growth factor (CTGF), fibronectin (FN) and α-smooth muscle actin (α-SMA). In addition, quinidine also decreased the Ang II-mediated elevation of concentration of intracellular Ca(2+) ([Ca(2+)]i) and extrusion of intracellular Mg(2+). Meanwhile, silencing SLC41A1 by RNA interference also impaired the elevation of [Ca(2+)]i, [Mg(2+)]i efflux and the upregulation of CTGF, FN and α-SMA provoked by Ang II. Furthermore, we found that Ang II-mediated activation of NFATc4 translocation decreased in SLC41A1-siRNA cells. These results support the notion that rapid extrusion of intracellular Mg(2+) is mediated by SLC41A1 and provide the evidence that the intracellular free Ca(2+) concentration is influenced by extrusion of intracellular Mg(2+) which facilitates fibrosis reaction in cardiac fibroblasts.

Rapamycin attenuated cardiac hypertrophy induced by isoproterenol and maintained energy homeostasis via inhibiting NF-κB activation.

Rapamycin, also known as sirolimus, is an immunosuppressant drug used to prevent rejection organ (especially kidney) transplantation. However, little is known about the role of Rapa in cardiac hypertrophy induced by isoproterenol and its underlying mechanism. In this study, Rapa was administrated intraperitoneally for one week after the rat model of cardiac hypertrophy induced by isoproterenol established. Rapa was demonstrated to attenuate isoproterenol-induced cardiac hypertrophy, maintain the structure integrity and functional performance of mitochondria, and upregulate genes related to fatty acid metabolism in hypertrophied hearts. To further study the implication of NF-κB in the protective role of Rapa, cardiomyocytes were pretreated with TNF-α or transfected with siRNA against NF-κB/p65 subunit. It was revealed that the upregulation of extracellular circulating proinflammatory cytokines induced by isoproterenol was able to be reversed by Rapa, which was dependent on NF-κB pathway. Furthermore, the regression of cardiac hypertrophy and maintaining energy homeostasis by Rapa in cardiomyocytes may be attributed to the inactivation of NF-κB. Our results shed new light on mechanisms underlying the protective role of Rapa against cardiac hypertrophy induced by isoproterenol, suggesting that blocking proinflammatory response by Rapa might contribute to the maintenance of energy homeostasis during the progression of cardiac hypertrophy.

The p65 subunit of NF-κB involves in RIP140-mediated inflammatory and metabolic dysregulation in cardiomyocytes.

The transcription factor NF-κB regulates expression of many genes that are involved in inflammation, fatty acid and glucose metabolism, and plays a crucial role in cardiac pathological processes. RIP140 is a corepressor that down-regulates expression of genes involved in the cellular substrate uptake and mitochondrial ß-oxidation. In addition to this, RIP140 also acts as a coactivator for p65-NF-κB, potentiating the secretion of proinflammatory cytokines in macrophages, but the effects in cardiomyocytes are still unknown. In this study, overexpression of RIP140 induced proinflammatory gene expression and cytokine release in neonatal rat cardiomyocytes, which could be reversed by p65-NF-κB inhibition. Furthermore, RIP140-mediated repression of metabolic-related genes, mitochondrial biogenesis and metabolic function were weakened after knocking down of p65-NF-κB. These findings suggest that p65-NF-κB plays an important role in RIP140-mediated proinflammatory response and energy metabolism in cardiomyocytes, and provide evidence for the crosstalk between proinflammatory processes and metabolic dysregulation in the heart.

C/EBPß knockdown protects cardiomyocytes from hypertrophy via inhibition of p65-NFκB.

C/EBPß, a member of the bHLH gene family of DNA-binding transcription factors, has been indicated as a central signal in physiologic hypertrophy. However, the role of C/EBPß in pathological cardiac hypertrophy remains to be elucidated. In this study, we revealed that C/EBPß is involved in cardiac hypertrophy, the expression of C/EBPß were significantly increased in response to hypertrophic stimulation in vitro and in vivo. C/EBPß knockdown inhibited PE-induced cardiac hypertrophy, and diminished the nuclear translocation and DNA binding activity of p65-NFκB. These results suggested that C/EBPß knockdown protected cardiomyocytes from hypertrophy, which may be attributed to inhibition of NFκB-dependent transcriptional activity. These findings shed new light on the understanding of C/EBPß-related cardiomyopathy, and suggest the potential application of C/EBPß inhibitors in cardiac hypertrophy.

Salvianolic acid B protects cardiomyocytes from angiotensin II-induced hypertrophy via inhibition of PARP-1.

Salvianolic acid B (SalB), one of the major bioactive components in Salviamiltiorrhiza, has plenty of cardioprotective effects. The present study was designed to investigate the effect of SalB on angiotensin II (AngII)-induced hypertrophy in neonatal rat cardiomyocytes, and to find out whether or not this effect is attributed to inhibition of poly (ADP-ribose) polymerase-1 (PARP-1), which plays a key role in cardiac hypertrophy. Our results showed that SalB prevented the cardiomyocytes from AngII-induced hypertrophy, associated with attenuation of the mRNA expressions of atrial natriuretic factor and brain natriuretic peptide, and reduction in the cell surface area. SalB inhibited the activity of PARP-1. The inhibitory effect was comparable to that of the PARP-1 inhibitor 3-Aminobenzamide (3-AB). In addition, SalB reversed the depletion of cellular NAD(+) induced by AngII. Moreover, overexpression of PARP-1 attenuated the anti-hypertrophic effect of SalB. These observations suggested that SalB prevented the cardiomyocytes from AngII-induced hypertrophy, at least partially through inhibition of PARP-1. Moreover, SalB attenuated the generation of oxidative stress via suppression of NADPH oxidase 2 and 4, which might probably contribute to the inhibition of PARP-1. These present findings may shed new light on the understanding of the cardioprotective effect of SalB.