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Myocardial ATGL overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction.

ABSTRACT: Alterations in myocardial triacylglycerol content have been associated with poor left ventricular function, suggesting that enzymes involved in myocardial triacylglycerol metabolism play an important role in regulating contractile function. Myocardial triacylglycerol catabolism is mediated by adipose triglyceride lipase (ATGL), which is rate limiting for triacylglycerol hydrolysis. To address the influence of triacylglycerol hydrolysis on myocardial energy metabolism and function, we utilized mice with cardiomyocyte-specific ATGL overexpression (MHC-ATGL). Biochemical examination of MHC-ATGL hearts revealed chronically reduced myocardial triacylglycerol content but unchanged levels of long-chain acyl coenzyme A esters, ceramides, and diacylglycerols. Surprisingly, fatty acid oxidation rates were decreased in ex vivo perfused working hearts from MHC-ATGL mice, which was compensated by increased rates of glucose oxidation. Interestingly, reduced myocardial triacylglycerol content was associated with moderately enhanced in vivo systolic function in MHC-ATGL mice and increased isoproterenol-induced cell shortening of isolated primary cardiomyocytes. Most importantly, MHC-ATGL mice were protected from pressure overload-induced systolic dysfunction and detrimental structural remodeling following transverse aortic constriction. Overall, this study shows that ATGL overexpression is sufficient to alter myocardial energy metabolism and improve cardiac function.

SUBMITTER: Kienesberger PC

PROVIDER: S-EPMC3272983 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Myocardial ATGL overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction.

Kienesberger Petra C PC Pulinilkunnil Thomas T Sung Miranda M Y MM Nagendran Jeevan J Haemmerle Guenter G Kershaw Erin E EE Young Martin E ME Light Peter E PE Oudit Gavin Y GY Zechner Rudolf R Dyck Jason R B JR

Molecular and cellular biology 20111212 4

Alterations in myocardial triacylglycerol content have been associated with poor left ventricular function, suggesting that enzymes involved in myocardial triacylglycerol metabolism play an important role in regulating contractile function. Myocardial triacylglycerol catabolism is mediated by adipose triglyceride lipase (ATGL), which is rate limiting for triacylglycerol hydrolysis. To address the influence of triacylglycerol hydrolysis on myocardial energy metabolism and function, we utilized mi ...[more]

PMID: 22158969

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Project description:Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4 weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. TAC-induced downregulation of ATGL results in increased proteasome (β1i/β2i/β5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.

Project description:Background SENP1 (sentrin/small ubiquitin-like modifier-specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload-induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac-specific SENP1 knockdown markedly exacerbated transverse aortic constriction-induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus-mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1-JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte-specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy-promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post-transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload-induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

Project description:Adipose tissue lipolysis occurs during the development of heart failure as a consequence of chronic adrenergic stimulation. However, the impact of enhanced adipose triacylglycerol hydrolysis mediated by adipose triglyceride lipase (ATGL) on cardiac function is unclear. To investigate the role of adipose tissue lipolysis during heart failure, we generated mice with tissue-specific deletion of ATGL (atATGL-KO). atATGL-KO mice were subjected to transverse aortic constriction (TAC) to induce pressure-mediated cardiac failure. The cardiac mouse lipidome and the human plasma lipidome from healthy controls (n = 10) and patients with systolic heart failure (HFrEF, n = 13) were analyzed by MS-based shotgun lipidomics. TAC-induced increases in left ventricular mass (LVM) and diastolic LV inner diameter were significantly attenuated in atATGL-KO mice compared to wild type (wt) -mice. More importantly, atATGL-KO mice were protected against TAC-induced systolic LV failure. Perturbation of lipolysis in the adipose tissue of atATGL-KO mice resulted in the prevention of the major cardiac lipidome changes observed after TAC in wt-mice. Profound changes occurred in the lipid class of phosphatidylethanolamines (PE) in which multiple PE-species were markedly induced in failing wt-hearts, which was attenuated in atATGL-KO hearts. Moreover, selected heart failure-induced PE species in mouse hearts were also induced in plasma samples from patients with chronic heart failure. TAC-induced cardiac PE induction resulted in decreased PC/ PE-species ratios associated with increased apoptotic marker expression in failing wt-hearts, a process absent in atATGL-KO hearts. Perturbation of adipose tissue lipolysis by ATGL-deficiency ameliorated pressure-induced heart failure and the potentially deleterious cardiac lipidome changes that accompany this pathological process, namely the induction of specific PE species. Non-cardiac ATGL-mediated modulation of the cardiac lipidome may play an important role in the pathogenesis of chronic heart failure.

Project description:BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles (EVs) including small EVs, or exosomes and their molecular cargo are known to modulate cell to cell communication during multiple cardiac diseases. However, the role of systemic EV biogenesis inhibition in the models of HF is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of Tipifarnib (Tip), a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a, nSmase2 and Alix) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery, were randomly assigned to groups with and without Tip treatment (10 mg/kg three times/week) and monitored for 8 weeks and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular (LV) dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced LV dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of Tip in TAC mice reduced circulating exosomes to baseline and remarkably improved LV functions, hypertrophy, and fibrosis. Tip treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR331-5p which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR331-5p is crucial for inhibiting fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR331-5p that acts as potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling to HF.

Dataset Information

Myocardial ATGL overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction.

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Myocardial ATGL overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction.

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