Role of the ubiquitin-proteasome system in the pathogenesis of cardiac hypertrophy and aging

Cardiovascular disease causes the highest morbidity and mortality worldwide. Moreover, the prevalence of cardiac hypertrophy and failure dramatically increases with aging, most notably in women. In this context, impairment of the ubiquitin-proteasome system (UPS) is supposed to be a pivotal element in the reinforcement of aging. Moreover, an involvement of the UPS, which accounts for the preservation of cardiomyocyte structure and function by the targeted degradation of structural, functional as well as signaling proteins, in the development of cardiac hypertrophy has been suggested. However, the number of systematic studies with regard to mechanisms underlying proteasome regulation in the heart and their role in cardiac remodeling, especially in the aging heart, is currently limited. Ongoing studies in our group reveal that cardiac hypertrophy due to continuous β-adrenergic stimulation in the mouse is exaggerated by knockout of the proteasome subunit β1i. The present study therefore addresses the question whether it is the absence of β1i incorporation into active cardiac proteasome complexes or its deficiency per se, which augments cardiac hypertrophy in β1i deficient mice upon treatment with isoprenaline. Reintroduction of β1i into cardiac proteasome complexes of β1i deficient mice by way of cardiac specific (serotype 9) adeno associated viral gene transfer resulted in reduced hypertrophy development, comparable to the level in isoprenaline-treated wild type mice, and prevention of a manifest systolic and diastolic dysfunction. Presumably, the augmented hypertrophy development in the isoprenaline treated β1i deficient mice is not related to a disturbance of the sarcomeric structure or a dysregulated degradation of contractile proteins. However, reassembly of β1i into active cardiac proteasome complexes seems to be associated with higher intracellular troponin I levels compared to the control group, which may contribute to the maintenance of cardiac function. In contrast to previous studies, marked alterations of the cardiac proteome associated with strongly increased 26S proteasome activities were detected in aging mouse hearts. Moreover, this increase in 26S proteasome activities seemed adaptive with respect to the extent of the alterations in the cardiac proteome, which may be associated with the age related deterioration of the general health status of these animals. This increase in 26S proteasome activities may thus serve to maintain protein homeostasis and cardiac function during aging. In conclusion, the present study revealed for the first time that increased incorporation of β1i into active cardiac proteasome complexes following induction of hypertrophy seems to be an important protective mechanism in maladaptive cardiac remodeling. Moreover, regulation of cardiac proteasome function during aging seems more complex than expected. Collectively, the current findings highlight how important it is to gain a better insight into mechanisms that regulate proteasome function in the context of aging and the pathogenesis of heart disease

Genetic ablation of Lmp2 increases the susceptibility for impaired cardiac function

Proteasome degradation is an integral part of cellular growth and function. Proteasomal intervention may mitigate adverse myocardial remodeling, but is associated with the onset of heart failure. Previously, we have demonstrated that increasing abundance of cardiac Lmp2 and its incorporation into proteasome complexes is an endogenous mechanism for proteasome regulation during hypertrophic remodeling of the heart induced by chronic ß-adrenoreceptor stimulation. Here, we investigated whether Lmp2 is required for myocardial remodeling not driven by inflammation and show that Lmp2 is a tipping element for growth and function in the heart but not for proteasome insufficiency. While it has no apparent impact under unchallenged conditions, myocardial remodeling without Lmp2 exacerbates hypertrophy and restricts cardiac function. Under chronic ß-adrenoreceptor stimulation, as seen in the development of cardiovascular disease and the manifestation of heart failure, genetic ablation of Lmp2 in mice caused augmented concentric hypertrophy of the left ventricle. While the heart rate was similarly elevated as in wildtype, myocardial contractility was not maintained without Lmp2, and apparently uncoupled of the ß-adrenergic response. Normalized to the exacerbated myocardial mass, contractility was reduced by 41% of the pretreatment level, but would appear preserved at absolute level. The lack of Lmp2 interfered with elevated 26S proteasome activities during early cardiac remodeling reported previously, but did not cause bulk proteasome insufficiency, suggesting the Lmp2 containing proteasome subpopulation is required for a selected group of proteins to be degraded. In the myocardial interstitium, augmented collagen deposition suggested matrix stiffening in the absence of Lmp2. Indeed, echocardiography of left ventricular peak relaxation velocity (circumferential strain rate) was reduced in this treatment group. Overall, targeting Lmp2 in a condition mimicking chronic ß-adrenoreceptor stimulation exhibited the onset of heart failure. Anticancer therapy inhibiting proteasome activity, including Lmp2, is associated with adverse cardiac events, in particular heart failure. Sparing Lmp2 may be an avenue to reduce adverse cardiac events when chronic sympathetic nervous system activation cannot be excluded

MiR-155-5p and MiR-203a-3p Are Prognostic Factors in Soft Tissue Sarcoma

Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%. Reliable molecular markers for risk stratification and subsequent therapy management are still needed. Therefore, we analyzed the prognostic potential of miR-155-5p and miR-203a-3p expression in a cohort of 79 STS patients. MiR-155-5p and miR-203a-3p expression was measured from tumor total RNA by qPCR and correlated with the demographic, clinicopathological, and prognostic data of the patients. Elevated miR-155-5p expression was significantly associated with increased tumor stage and hypoxia-associated mRNA/protein expression. High miR-155-5p expression and low miR-203a-3p expression, as well as a combination of high miR-155-5p and low miR-203a-3p expression, were significantly associated with poor disease-specific survival in STS patients in the Kaplan–Meier survival analyses (p = 0.027, p = 0.001 and p = 0.0003, respectively) and in the univariate Cox regression analyses (RR = 1.96; p = 0.031; RR = 2.59; p = 0.002 and RR = 4.76; p = 0.001, respectively), but not in the multivariate Cox regression analyses. In conclusion, the oncomiR miR-155-5p and the tumor suppressor-miR miR-203a-3p exhibit an association with STS patient prognosis and are suggested as candidates for risk assessment

Acetylation and phosphorylation changes to cardiac proteins in experimental HFpEF due to metabolic risk reveal targets for treatment

Aims: Despite the high prevalence of heart failure with preserved ejection fraction (HFpEF), the pathomechan-isms remain elusive and specific therapy is lacking. Disease-causing factors include metabolic risk, notably obesity. However, proteomic changes in HFpEF are poorly understood, hampering therapeutic strategies. We sought to elucidate how metabolic syndrome affects cardiac protein expression, phosphorylation and acetylation in the Zucker diabetic fatty/Spontaneously hypertensive heart failure F1 (ZSF1) rat HFpEF model, and to evaluate changes regarding their potential for treatment.Main methods: ZSF1 obese and lean rats were fed a Purina diet up to the onset of HFpEF in the obese animals. We quantified the proteome, phosphoproteome and acetylome of ZSF1 obese versus lean heart tissues by mass spectrometry and singled out targets for site-specific evaluation.Key findings: The acetylome of ZSF1 obese versus lean hearts was more severely altered (21 % of proteins changed) than the phosphoproteome (9 %) or proteome (3 %). Proteomic alterations, confirmed by immuno-blotting, indicated low-grade systemic inflammation and endothelial remodeling in obese hearts, but low nitric oxide-dependent oxidative/nitrosative stress. Altered acetylation in ZSF1 obese hearts mainly affected pathways important for metabolism, energy production and mechanical function, including hypo-acetylation of mechan-ical proteins but hyper-acetylation of proteins regulating fatty acid metabolism. Hypo-acetylation and hypo-phosphorylation of elastic titin in ZSF1 obese hearts could explain myocardial stiffening.Significance: Cardiometabolic syndrome alters posttranslational modifications, notably acetylation, in experi-mental HFpEF. Pathway changes implicate a HFpEF signature of low-grade inflammation, endothelial dysfunction, metabolic and mechanical impairment, and suggest titin stiffness and mitochondrial metabolism as promising therapeutic targets

Perspectives in visual imaging for marine biology and ecology: from acquisition to understanding

http://www.godac.jamstec.go.jp/darwin/cruise/kairei/kr12-07/

Nicotinamide for the treatment of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD(+)). Elevating NAD(+) by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD(+) precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD(+) precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans