Cardiomyocyte p38 MAPKα suppresses a heart-adipose tissue-neutrophil crosstalk in heart failure development.

Although p38 MAP Kinase α (p38 MAPKα) is generally accepted to play a central role in the cardiac stress response, to date its function in maladaptive cardiac hypertrophy is still not unambiguously defined. To induce a pathological type of cardiac hypertrophy we infused angiotensin II (AngII) for 2 days via osmotic mini pumps in control and tamoxifen-inducible, cardiomyocyte (CM)-specific p38 MAPKα KO mice (iCMp38αKO) and assessed cardiac function by echocardiography, complemented by transcriptomic, histological, and immune cell analysis. AngII treatment after inactivation of p38 MAPKα in CM results in left ventricular (LV) dilatation within 48 h (EDV: BL: 83.8 ± 22.5 µl, 48 h AngII: 109.7 ± 14.6 µl) and an ectopic lipid deposition in cardiomyocytes, reflecting a metabolic dysfunction in pressure overload (PO). This was accompanied by a concerted downregulation of transcripts for oxidative phosphorylation, TCA cycle, and fatty acid metabolism. Cardiac inflammation involving neutrophils, macrophages, B- and T-cells was significantly enhanced. Inhibition of adipose tissue lipolysis by the small molecule inhibitor of adipocytetriglyceride lipase (ATGL) Atglistatin reduced cardiac lipid accumulation by 70% and neutrophil infiltration by 30% and went along with an improved cardiac function. Direct targeting of neutrophils by means of anti Ly6G-antibody administration in vivo led to a reduced LV dilation in iCMp38αKO mice and an improved systolic function (EF: 39.27 ± 14%). Thus, adipose tissue lipolysis and CM lipid accumulation augmented cardiac inflammation in iCMp38αKO mice. Neutrophils, in particular, triggered the rapid left ventricular dilatation. We provide the first evidence that p38 MAPKα acts as an essential switch in cardiac adaptation to PO by mitigating metabolic dysfunction and inflammation. Moreover, we identified a heart-adipose tissue-immune cell crosstalk, which might serve as new therapeutic target in cardiac pathologies.

Atglistatin Pretreatment Preserves Remote Myocardium Function Following Myocardial Infarction.

The pathological role of adipose derived fatty acids following myocardial infarction has long been hypothesized. However, most methods for reducing adipocyte lipolysis have significant non-adipose effects. Atglistatin, a direct inhibitor of the initial lipase in the lipolysis cascade, has been recently shown to inhibit adipose tissue lipolysis after oral administration. To explore the ability of Atglistatin to impact the pathophysiology of cardiac ischemia we performed prophylactic treatment of mice with Atglistatin for 2 days before 1-hour cardiac ischemia. After 7 days of reperfusion, hearts of Atglistatin treated mice showed significantly improved systolic pump function while infarct and scar size were unaffected. Strain analysis of echocardiographic data revealed an enhanced performance of the remote myocardium as cause for overall improved systolic function. The present study provides evidence that inhibition of adipocyte adipose triglyceride lipase (ATGL) using Atglistatin is able to improve cardiac function after MI by targeting the remote myocardium.

Adipocyte lipolysis drives acute stress-induced insulin resistance.

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.

Proteins regulating the intercellular transfer and function of P-glycoprotein in multidrug-resistant cancer.

Chemotherapy is an essential part of anticancer treatment. However, the overexpression of P-glycoprotein (P-gp) and the subsequent emergence of multidrug resistance (MDR) hampers successful treatment clinically. P-gp is a multidrug efflux transporter that functions to protect cells from xenobiotics by exporting them out from the plasma membrane to the extracellular space. P-gp inhibitors have been developed in an attempt to overcome P-gp-mediated MDR; however, lack of specificity and dose limiting toxicity have limited their effectiveness clinically. Recent studies report on accessory proteins that either directly or indirectly regulate P-gp expression and function and which are necessary for the establishment of the functional phenotype in cancer cells. This review discusses the role of these proteins, some of which have been recently proposed to comprise an interactive complex, and discusses their contribution towards MDR. We also discuss the role of other pathways and proteins in regulating P-gp expression in cells. The potential for these proteins as novel therapeutic targets provides new opportunities to circumvent MDR clinically.

Deciphering Cell-to-Cell Communication in Acquisition of Cancer Traits: Extracellular Membrane Vesicles Are Regulators of Tissue Biomechanics.

Deciphering the role of cell-to-cell communication in acquisition of cancer traits such as metastasis is one of the key challenges of integrative biology and clinical oncology. In this context, extracellular vesicles (EVs) are important vectors in cell-to-cell communication and serve as conduits in the transfer of cellular constituents required for cell function and for the establishment of cellular phenotypes. In the case of malignancy, they have been shown to support the acquisition of common traits defined as constituting the hallmarks of cancer. Cellular biophysics has contributed to our understanding of some of these central traits with changes in tissue biomechanics reflective of cell state. Indeed, much is known about stiffness of the tissue scaffold in the context of cell invasion and migration. This article advances this knowledge frontier by showing for the first time that EVs are mediators of tissue biomechanical properties and, importantly, demonstrates a link between the acquisition of cancer multidrug resistance and increased tissue stiffness of the malignant mass. The methodology used in the study employed optical coherence elastography and atomic force microscopy on breast cancer cell monolayers and tumor spheroids. Specifically, we show here that the acquired changes in tissue stiffness can be attributed to the intracellular transfer of a protein complex comprising ezrin, radixin, moesin, CD44, and P-glycoprotein. This has important implications in facilitating mechano-transduced signaling cascades that regulate the acquisition of cancer traits, such as invasion and metastasis. Finally, this study also introduces novel targets and strategies for diagnostic and therapeutic innovation in oncology, with a view to prevention of metastatic spread and personalized medicine in cancer treatment.