Explore the vast range of titles available.

Lipolysis of triglyceride‐rich lipoproteins by peripheral lipoprotein lipase (LPL) plays an essential role in maintaining systemic cholesterol/lipid homeostasis. Human genetic studies have unequivocally demonstrated that activation of LPL pathway reduces risks for both coronary artery disease (CAD) and type 2 diabetes (T2D). Although sterol regulatory element‐binding protein 2 (SREBP2) is well established as the master transcription factor that regulates the hepatic biosynthesis of both cholesterol and fatty acids, whether and how its activity in liver interacts with peripheral LPL pathway remains unknown. Here, it is demonstrated that acute liver‐specific depletion of SREBP2 results in divergent effects on the regulation of peripheral LPL activity in mice, depending on the presence or absence of low‐density lipoprotein receptors (LDLR). SREBP2 deficiency drastically elevates peripheral LPL activity through downregulation of plasma angiopoietin‐related protein 3 (ANGPTL3) levels in LDLR‐deficient mice. Moreover, in addition to SREBP2's transcriptional regulation of ANGPTL3, it is found that SREBP2 promotes proteasome‐based degradation of ANGPTL3 in the presence of LDLR. Remarkably, acute depletion of hepatic SREBP2 protects against hypercholesterolemia and atherosclerosis, in which atherosclerotic lesions are reduced by 45% compared to control littermates. Taken together, these findings outline a liver‐peripheral crosstalk mediated by SREBP2‐ANGPTL3‐LPL axis and suggest that SREBP2 inhibition can be an effective strategy to tackle homozygous familial hypercholesterolemia (HoFH). This study reveals a novel crosstalk between hepatic SREBP2‐mediated cholesterol biosynthesis pathway and peripheral lipoprotein lipase‐mediated lipolysis pathway in the regulation of systemic lipid metabolism. Notably, the lipid‐lowering effects of SREBP2 inhibition are independent of a functional LDL receptor, highlighting the potential of acute hepatic SREBP2 depletion as a promising therapeutic strategy for managing homozygous familial hypercholesterolemia.

Rho GTPases and Hippo kinases are key regulators of cardiomyoblast differentiation. However, how these signaling axes are coordinated spatiotemporally remains unclear. Here, the central and multifaceted roles of the BCH domain containing protein, BNIP‐2, in orchestrating the expression of two key cardiac genes (cardiac troponin T [cTnT] and cardiac myosin light chain [Myl2]) in H9c2 and human embryonic stem cell‐derived cardiomyocytes are delineated. This study shows that BNIP‐2 mRNA and protein expression increase with the onset of cTnT and Myl2 and promote the alignment of H9c2 cardiomyocytes. Mechanistically, BNIP‐2 is required for the inactivation of YAP through YAP phosphorylation and its cytosolic retention. Turbo‐ID proximity labeling corroborated by super‐resolution analyses and biochemical pulldown data reveals a scaffolding role of BNIP‐2 for LATS1 to phosphorylate and inactivate YAP in a process that requires BNIP‐2 activation of cellular contractility. The findings identify BNIP‐2 as a pivotal signaling scaffold that spatiotemporally integrates RhoA/Myosin II and LATS1/YAP mechanotransduction signaling to drive cardiomyoblast differentiation, by switching the genetic programming from YAP‐dependent growth to YAP‐silenced differentiation. These findings offer insights into the importance of scaffolding proteins in bridging the gap between mechanical and biochemical signals in cell growth and differentiation and the prospects in translational applications. Proper heart formation requires distinct steps of cardiomyocyte proliferation followed by terminal differentiation. This study identifies the scaffold protein, BNIP‐2, as a regulator of this process by performing multifaceted roles in regulating biochemical and mechanotransduction pathways. BNIP‐2 scaffolding of LATS1 and YAP is required to inactivate YAP to induce cardiac genes. Concomitantly, BNIP‐2 regulation of force through RhoA is required for BNIP‐2, LATS1 and LATS1, YAP interaction.

The mammalian heart contains heterogeneous cell types contributing to pathological changes in cardiac disease. In this Comment, we explore how single-cell transcriptomic approaches are unveiling intricate cellular mechanisms and gene co-expression networks that regulate the workings, and failings, of the heart.

Cardiac regeneration may revolutionize treatment for heart failure but endogenous progenitor-derived cardiomyocytes in the adult mammalian heart are few and pre-existing adult cardiomyocytes divide only at very low rates. Although candidate genes that control cardiomyocyte cell cycle re-entry have been implicated, expression heterogeneity in the cardiomyocyte stress-response has never been explored. Here, we show by single nuclear RNA-sequencing of cardiomyocytes from both mouse and human failing, and non-failing adult hearts that sub-populations of cardiomyocytes upregulate cell cycle activators and inhibitors consequent to the stress-response in vivo. We characterize these subgroups by weighted gene co-expression network analysis and discover long intergenic non-coding RNAs (lincRNA) as key nodal regulators. KD of nodal lincRNAs affects expression levels of genes related to dedifferentiation and cell cycle, within the same gene regulatory network. Our study reveals that sub-populations of adult cardiomyocytes may have a unique endogenous potential for cardiac regeneration in vivo. Adult mammalian cardiomyocytes are predominantly binucleated and unable to divide. Using single nuclear RNA-sequencing of cardiomyocytes from mouse and human failing and non-failing adult hearts, See et al. show that some cardiomyocytes respond to stress by dedifferentiation and cell cycle re-entry regulated by lncRNAs.

Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating'these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter-enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health.

Background Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy. Methods We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfβ/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment. Results Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation. Conclusions In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM. Graphical Abstract Highlights After evaluation of 14 potential candidates in a cardiac-specific Lmna DCM model, we demonstrated that Smad3 shRNA, Yy1 , combination of Bmp7 and Ctgf ( Bmp7 - Ctgf shRNA), Yap1 , Sun1 shRNA, Lamin A, and Lamin C improved cardiac function. Sun1 shRNA and Lamin C particularly prolonged a long-term survival. We uncovered that inflammation and DNA damage markers were among the top list of highly correlated markers in addition to traditional HF and fibrosis markers, suggesting these additional markers are important to evaluate the candidates for the treatment efficacy of LMNA DCM. The study revealed that treating Lmna DCM with Lamin A did not work as expected and had toxic effects. The toxicity was found to be dose-dependent and not caused by prelamin A processing.

In vivo SELEX is an advanced adaptation of Systematic Evolution of Ligands by Exponential Enrichment (SELEX) that allows the development of aptamers capable of recognizing targets directly within their natural microenvironment. While this methodology ensures a higher translation potential for the selected aptamer, it does not select for aptamers that recognize specific cell types within a tissue. Such aptamers could potentially improve the development of drugs for several diseases, including neuromuscular disorders, by targeting solely the proteins involved in their pathogenesis. Here, we describe our attempt to utilize in vivo SELEX with a modification in the methodology that drives the selection of intravenously injected aptamers towards a specific cell type of interest. Our data suggest that the incorporation of a cell enrichment step can direct the in vivo localization of RNA aptamers into cardiomyocytes, the cardiac muscle cells, more readily over other cardiac cells. Given the crucial role of cardiomyocytes in the disease pathology in DMD cardiomyopathy and therapy, these aptamers hold great potential as drug delivery vehicles with cardiomyocyte selectivity.

Through extensive multisystem phenotyping, the central aim of Project PICMAN is to correlate metabolic flexibility to measures of cardiometabolic health, including myocardial diastolic dysfunction, coronary and cerebral atherosclerosis, body fat distribution and severity of non-alcoholic fatty liver disease. This cohort will form the basis of larger interventional trials targeting metabolic inflexibility in the prevention of cardiovascular disease. Participants aged 21–72 years with no prior manifest atherosclerotic cardiovascular disease (ASCVD) are being recruited from a preventive cardiology clinic and an existing cohort of non-alcoholic fatty liver disease (NAFLD) in an academic medical centre. A total of 120 patients will be recruited in the pilot phase of this study and followed up for 5 years. Those with 10-year ASCVD risk ≥ 5% as per the QRISK3 calculator are eligible. Those with established diabetes mellitus are excluded. Participants recruited undergo a detailed assessment of health behaviours and physical measurements. Participants also undergo a series of multimodality clinical phenotyping comprising cardiac tests, vascular assessments, metabolic tests, liver and neurovascular testing. Blood samples are also being collected and banked for plasma biomarkers, ‘multi-omics analyses’ and for generation of induced pluripotent stem cells (iPSC). Extensive evidence points to metabolic dysregulation as an early precursor of cardiovascular disease, particularly in Asia. We hypothesise that quantifiable metabolic inflexibility may be representative of an individual in his/her silent, but high-risk progression towards insulin resistance, diabetes and cardiovascular disease. The platform for interdisciplinary cardiovascular-metabolic-neurovascular diseases (PICMAN) is a pilot, prospective, multi-ethnic cohort study.

Doxorubicin is an anthracycline widely used for the treatment of various cancers; however, the drug has a common deleterious side effect, namely a dose-dependent cardiotoxicity. Doxorubicin treatment increases the generation of reactive oxygen species, which leads to oxidative stress in the cardiac cells and ultimately DNA damage and cell death. The most common DNA lesion produced by oxidative stress is 7,8-dihydro-8-oxoguanine (8-oxoguanine), and the enzyme responsible for its repair is the 8-oxoguanine DNA glycosylase (OGG1), a base excision repair enzyme. Here, we show that the OGG1 deficiency has no major effect on cardiac function at baseline or with pressure overload; however, we found an exacerbation of cardiac dysfunction as well as a higher mortality in Ogg1 knockout mice treated with doxorubicin. Our transcriptomic analysis also showed a more extensive dysregulation of genes in the hearts of Ogg1 knockout mice with an enrichment of genes involved in inflammation. These results demonstrate that OGG1 attenuates doxorubicin-induced cardiotoxicity and thus plays a role in modulating drug-induced cardiomyopathy.

BNIP‐2 Activation of Cellular Contractility In article number 2202834 by Darren Chen Pei Wong, Pakorn Kanchanawong, Boon Chuan Low, and co‐workers, the multifaceted roles of the scaffold protein, BNIP‐2, are demonstrated to induce the expression of two cardiac markers, cTnT and Myl2, in H9c2 and hESC cells. During this process, BNIP‐2 activation of contractility and scaffolding of LATS1 to Yes‐associated protein (YAP) is required to inactivate YAP for cardiomyoblast differentiation.