Jana Grune

Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate

Background: Endurance training induces physiological cardiac hypertrophy and elevates adipose tissue lipolysis. Results: Adipose-specific adipose triglyceride lipase (Atgl)-knock-out mice exhibit attenuated exercise-induced cardiac hypertrophy likely mediated by the lack of C16:1n7 palmitoleate actions on the heart. Conclusion: Atgl-mediated adipose lipolysis regulates physiological cardiac hypertrophy. Significance: Adipose-derived lipokines may serve as important molecular mediators of cardiac physiology and pathology. Endurance exercise training induces substantial adaptive cardiac modifications such as left ventricular hypertrophy (LVH). Simultaneously to the development of LVH, adipose tissue (AT) lipolysis becomes elevated upon endurance training to cope with enhanced energy demands. In this study, we investigated the impact of adipose tissue lipolysis on the development of exercise-induced cardiac hypertrophy. Mice deficient for adipose triglyceride lipase (Atgl) in AT (atATGL-KO) were challenged with chronic treadmill running. Exercise-induced AT lipolytic activity was significantly reduced in atATGL-KO mice accompanied by the absence of a plasma fatty acid (FA) increase. These processes were directly associated with a prominent attenuation of myocardial FA uptake in atATGL-KO and a significant reduction of the cardiac hypertrophic response to exercise. FA serum profiling revealed palmitoleic acid (C16:1n7) as a new molecular co-mediator of exercise-induced cardiac hypertrophy by inducing nonproliferative cardiomyocyte growth. In parallel, serum FA analysis and echocardiography were performed in 25 endurance athletes. In consonance, the serum C16:1n7 palmitoleate level exhibited a significantly positive correlation with diastolic interventricular septum thickness in those athletes. No correlation existed between linoleic acid (18:2n6) and diastolic interventricular septum thickness. Collectively, our data provide the first evidence that adipose tissue lipolysis directly promotes the development of exercise-induced cardiac hypertrophy involving the lipokine C16:1n7 palmitoleate as a molecular co-mediator. The identification of a lipokine involved in physiological cardiac growth may help to develop future lipid-based therapies for pathological LVH or heart failure.

PCSK9 regulates the chemokine receptor CCR2 on monocytes

Monocyte migration is a key element in atherosclerosis. LDL-C facilitates monocyte migration via induction of CCR2. PCSK9 regulates cell surface expression of the LDL-R and is expressed in vascular smooth muscle cells (VSMCs). The present study was done to investigate the regulation of PCSK9 in VSMCs and its impact on monocyte function. METHODS AND RESULTS PCSK9 mRNA and protein levels were upregulated in VSMCs by the TLR-4 ligand LPS, whereas TGF-β or angiotensin II had no effect. Induction of PCSK9 was selectively inhibited by TLR-4 blockade and further downstream by the SAPK/JNK-inhibitor SP600125, whereas inhibitors of ERK1/2, p38 or PI3-kinase pathways had no effect. Incubation of monocytes in conditioned media from LPS-stimulated VSMCs resulted in a significant reduction of LDL-R levels on monocytes, comparable to the effects of recombinant PCSK9. LDL-C increased monocyte CCR2 expression, which augmented monocyte migration towards MCP-1. This LDL-C dependent monocyte chemotaxis was inhibited by supernatants from LPS-stimulated VSMCs, similar to recombinant PCSK9 and a specific LDL-R blocking antibody. CONCLUSION PCSK9 is regulated in VSMCs by TLR-4 - SAPK/JNK signaling, a pathway important in inflammation and metabolism. VSMC-derived PCSK9 reduces monocyte LDL-R expression, affecting LDL-C/LDL-R-mediated CCR2-expression on monocytes, which is crucial to cell motility and atherogenesis.

Application of Speckle-Tracking Echocardiography in an Experimental Model of Isolated Subendocardial Damage

Background: The subendocardium is highly vulnerable to damage and is thus affected even in subclinical disease stages. Therefore, methods reflecting subendocardial status are of great clinical relevance for the early detection of cardiac damage and the prevention of functional impairment. The aim of this study was to investigate the potential ability of myocardial strain parameters to evaluate changes within the subendocardium. Methods: Male 129/Sv mice were injected with isoproterenol (ISO; n = 32) to induce isolated subendocardial fibrotic lesions or saline as appropriate control (n = 15). Transthoracic echocardiography was performed using a 30‐MHz linear‐frequency transducer coupled to a high‐resolution imaging system, and acquired images were analyzed for conventional and strain parameters. The degree of collagen content within the different cardiac layers was quantified by histologic analysis and serum levels of tissue inhibitor of metalloproteinase–1, a biomarker for fibrosis, were assessed. Results: ISO treatment induced a marked increase in subendocardial collagen content in response to cell loss (control vs ISO, 0.6 ± 0.3% vs 5.8 ± 0.9%; P < .001) and resulted in a moderate increase in left ventricular wall thickness with preserved systolic function. Global longitudinal peak strain (LS) and longitudinal strain rate were significantly decreased in ISO‐treated animals (LS, −15.49% vs −11.49% [P = .001]; longitudinal strain rate, −4.81 vs −3.88 sec−1 [P < .05]), whereas radial and circumferential strain values remained unchanged. Global LS was associated with subendocardial collagen content (r = 0.46, P = .01) and tissue inhibitor of metalloproteinase–1 serum level (r = 0.52, P < .05). Further statistical analyses identified global LS as a superior predictor for the presence of subendocardial fibrosis (sensitivity, 84%; specificity, 80%; cutoff value, −14.4%). Conclusion: Assessment of LS may provide a noninvasive method for the detection of subendocardial damage and may consequently improve early diagnosis of cardiac diseases. HighlightsSTE was performed in an experimental model of isolated subendocardial fibrosis, and comprehensive morphologic‐functional correlation analyses were performed.Functional impairment was present only in decreased global LS and global LSR values, whereas global systolic function and other strain parameters remained unaffected.Global LS was associated with subendocardial collagen content and serum level of TIMP‐1.Global LS was identified as a superior predictor for the presence of subendocardial damage. Abbreviations: H&E = Hematoxylin and Eosin; ISO = Isoproterenol; LS = Longitudinal peak strain; LSR = Longitudinal strain rate; LV = Left ventricular; SBP = Systolic blood pressure; STE = Speckle‐tracking echocardiography; TIMP‐1 = Tissue inhibitor of metalloproteinase–1.

Adipose tissue ATGL modifies the cardiac lipidome in pressure-overload-induced left ventricular failure

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.

Selective Mineralocorticoid Receptor Cofactor Modulation as Molecular Basis for Finerenone’s Antifibrotic ActivityNovelty and Significance

Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in chronic heart failure. Novel nonsteroidal MRAs are currently developed and need to be pharmacologically characterized in comparison to classical steroidal MRAs. A mouse model of cardiac fibrosis induced by short-term isoproterenol injection was used to compare the nonsteroidal MRA finerenone and the steroidal MRA eplerenone in equi-efficient systemic MR blocking dosages. Molecular mechanisms were studied in MR-expressing H9C2/MR+ cardiomyocytes and in MR transcriptional cofactor binding assays. Both MRAs significantly inhibited an isoproterenol-mediated increase of left ventricular mass. Isoproterenol-induced cardiac fibrosis and macrophage invasion were potently blocked by finerenone, whereas eplerenone had no significant effect. Speckle tracking echocardiography revealed a significant improvement of global longitudinal peak strain by finerenone, an effect less prominent with eplerenone. Antifibrotic actions of finerenone were accompanied by a significant inhibition of profibrotic cardiac TNX (tenascin-X) expression, a regulation absent with eplerenone. Finally, we show a higher potency/efficacy and inverse agonism of finerenone versus eplerenone in MR transcriptional cofactor binding assays indicating differential MR cofactor modulation by steroidal and nonsteroidal MRAs. This study demonstrates that the nonsteroidal MRA finerenone potently prevents cardiac fibrosis and improves strain parameters in mice. Cardiac antifibrotic actions of finerenone may result from the inhibition of profibrotic TNX gene expression mediated by differential MR cofactor binding. Selective MR cofactor modulation provides a molecular basis for distinct (pre)-clinical actions of nonsteroidal and steroidal MRAs.

Is there a role for endothelin-1 receptor antagonists in the treatment of lung fibrosis associated with pulmonary hypertension?

Pulmonary hypertension (PH) is a multi-aetiological haemodynamic and pathophysiological condition defined as an increase in mean pulmonary artery pressure ≥25 mmHg at rest, and classified in five subgroups: 1) pulmonary arterial hypertension (PAH), 2) PH due to left heart disease, 3) PH due to lung disease and/or hypoxia, 4) chronic thromboembolic PH and 5) PH with unclear multifactorial mechanisms [1]. Over the past 20 years, a series of breakthrough therapeutic advances in PAH treatment paved the way for presently four approved drug classes. PAH, however, is a rare disease and the vast majority of PH patients belong to groups 2 and 3 [2], for which no effective therapies have so far been approved [3]. It is possible that macitentan has therapeutic effects in patients with advanced IPF and associated PH http://ow.ly/NYMs30loVxO