Recent Insights into the Role of PPARs in Disease.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play important roles in cell proliferation, differentiation, metabolism, and cancer [...].

Cardiomyocyte-Specific Wt1 Is Involved in Cardiac Metabolism and Response to Damage.

The Wilms tumor suppressor gene (Wt1) encodes a C2H2-type zinc-finger transcription factor that participates in transcriptional regulation, RNA metabolism, and protein-protein interactions. WT1 is involved in the development of several organs, including the kidneys and gonads, heart, spleen, adrenal glands, liver, diaphragm, and neuronal system. We previously provided evidence of transient WT1 expression in about 25% of cardiomyocytes of mouse embryos. Conditional deletion of Wt1 in the cardiac troponin T lineage caused abnormal cardiac development. A low expression of WT1 has also been reported in adult cardiomyocytes. Therefore, we aimed to explore its function in cardiac homeostasis and in the response to pharmacologically induced damage. Silencing of Wt1 in cultured neonatal murine cardiomyocytes provoked alterations in mitochondrial membrane potential and changes in the expression of genes related to calcium homeostasis. Ablation of WT1 in adult cardiomyocytes by crossing αMHCMerCreMer mice with homozygous WT1-floxed mice induced hypertrophy, interstitial fibrosis, altered metabolism, and mitochondrial dysfunction. In addition, conditional deletion of WT1 in adult cardiomyocytes increased doxorubicin-induced damage. These findings suggest a novel role of WT1 in myocardial physiology and protection against damage.

Molecular Mechanisms of Cardiac Development and Disease.

During development, the heart is the first organ to form and function [...].

Controversies and Recent Advances in Senescence and Aging.

Aging is the leading predictive factor of many chronic diseases that account for most of the morbidity and mortality worldwide, i [...].

Pharmacological Utility of PPAR Modulation for Angiogenesis in Cardiovascular Disease.

Peroxisome proliferator activated receptors, including PPARα, PPARß/δ, and PPARγ, are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They play important roles in glucose and lipid metabolism and are also supposed to reduce inflammation and atherosclerosis. All PPARs are involved in angiogenesis, a process critically involved in cardiovascular pathology. Synthetic specific agonists exist for all PPARs. PPARα agonists (fibrates) are used to treat dyslipidemia by decreasing triglyceride and increasing high-density lipoprotein (HDL) levels. PPARγ agonists (thiazolidinediones) are used to treat Type 2 diabetes mellitus by improving insulin sensitivity. PPARα/γ (dual) agonists are supposed to treat both pathological conditions at once. In contrast, PPARß/δ agonists are not in clinical use. Although activators of PPARs were initially considered to have favorable effects on the risk factors for cardiovascular disease, their cardiovascular safety is controversial. Here, we discuss the implications of PPARs in vascular biology regarding cardiac pathology and focus on the outcomes of clinical studies evaluating their benefits in cardiovascular diseases.

Editorial (Preface) "Cells/Cells of the Cardiovascular System-Editorial Highlights 2020-2021: The Book Selection".

This introduction provides a preface to the section on "Cells of the Cardiovascular System" in the book entitled "Editor's Choice Articles in 2020-2021" [...].

P16INK4A-More Than a Senescence Marker.

Aging is a biological feature that is characterized by gradual degeneration of function in cells, tissues, organs, or an intact organism due to the accumulation of environmental factors and stresses with time. Several factors have been attributed to aging such as oxidative stress and augmented production or exposure to reactive oxygen species, inflammatory cytokines production, telomere shortening, DNA damage, and, importantly, the deposit of senescent cells. These are irreversibly mitotically inactive, yet metabolically active cells. The reason underlying their senescence lies within the extrinsic and the intrinsic arms. The extrinsic arm is mainly characterized by the expression and the secretory profile known as the senescence-associated secretory phenotype (SASP). The intrinsic arm results from the impact of several genes meant to regulate the cell cycle, such as tumor suppressor genes. P16INK4A is a tumor suppressor and cell cycle regulator that has been linked to aging and senescence. Extensive research has revealed that p16 expression is significantly increased in senescent cells, as well as during natural aging or age-related pathologies. Based on this fact, p16 is considered as a specific biomarker for detecting senescent cells and aging. Other studies have found that p16 is not only a senescence marker, but also a protein with many functions outside of senescence and aging. In this paper, we discuss and shed light on several studies that show the different functions of p16 and provide insights in its role in several biological processes besides senescence and aging.

Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer.

Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.

The Editor's Choice Articles-Section "Cells of the Cardiovascular System" 2020-2021.

Cells is experiencing a rapid increase in attractiveness and impact [...].

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis.

It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.

Transcriptional Regulation of Cardiac Development and Disease.

The heart, which is the first organ to develop in the embryo, is indispensable for vital functions throughout life [...].

Dynamic Spatiotemporal Expression Pattern of the Senescence-Associated Factor p16Ink4a in Development and Aging.

A plethora of factors have been attributed to underly aging, including oxidative stress, telomere shortening and cellular senescence. Several studies have shown a significant role of the cyclin-dependent kinase inhibitor p16ink4a in senescence and aging. However, its expression in development has been less well documented. Therefore, to further clarify a potential role of p16 in development and aging, we conducted a developmental expression study of p16, as well as of p19ARF and p21, and investigated their expression on the RNA level in brain, heart, liver, and kidney of mice at embryonic, postnatal, adult, and old ages. P16 expression was further assessed on the protein level by immunohistochemistry. Expression of p16 was highly dynamic in all organs in embryonic and postnatal stages and increased dramatically in old mice. Expression of p19 and p21 was less variable and increased to a moderate extent at old age. In addition, we observed a predominant expression of p16 mRNA and protein in liver endothelial cells versus non-endothelial cells of old mice, which suggests a functional role specifically in liver endothelium of old subjects. Thus, p16 dynamic spatiotemporal expression might implicate p16 in developmental and physiological processes in addition to its well-known function in the build-up of senescence.

Every Beat You Take-The Wilms' Tumor Suppressor WT1 and the Heart.

Nearly three decades ago, the Wilms' tumor suppressor Wt1 was identified as a crucial regulator of heart development. Wt1 is a zinc finger transcription factor with multiple biological functions, implicated in the development of several organ systems, among them cardiovascular structures. This review summarizes the results from many research groups which allowed to establish a relevant function for Wt1 in cardiac development and disease. During development, Wt1 is involved in fundamental processes as the formation of the epicardium, epicardial epithelial-mesenchymal transition, coronary vessel development, valve formation, organization of the cardiac autonomous nervous system, and formation of the cardiac ventricles. Wt1 is further implicated in cardiac disease and repair in adult life. We summarize here the current knowledge about expression and function of Wt1 in heart development and disease and point out controversies to further stimulate additional research in the areas of cardiac development and pathophysiology. As re-activation of developmental programs is considered as paradigm for regeneration in response to injury, understanding of these processes and the molecules involved therein is essential for the development of therapeutic strategies, which we discuss on the example of WT1.

Small Activating RNAs: Towards the Development of New Therapeutic Agents and Clinical Treatments.

Small double-strand RNA (dsRNA) molecules can activate endogenous genes via an RNA-based promoter targeting mechanism. RNA activation (RNAa) is an evolutionarily conserved mechanism present in diverse eukaryotic organisms ranging from nematodes to humans. Small activating RNAs (saRNAs) involved in RNAa have been successfully used to activate gene expression in cultured cells, and thereby this emergent technique might allow us to develop various biotechnological applications, without the need to synthesize hazardous construct systems harboring exogenous DNA sequences. Accordingly, this thematic issue aims to provide insights into how RNAa cellular machinery can be harnessed to activate gene expression leading to a more effective clinical treatment of various diseases.

Implications of the Wilms' Tumor Suppressor Wt1 in Cardiomyocyte Differentiation.

The Wilms' tumor suppressor Wt1 is involved in multiple developmental processes and adult tissue homeostasis. The first phenotypes recognized in Wt1 knockout mice were developmental cardiac and kidney defects. Wt1 expression in the heart has been described in epicardial, endothelial, smooth muscle cells, and fibroblasts. Expression of Wt1 in cardiomyocytes has been suggested but remained a controversial issue, as well as the role of Wt1 in cardiomyocyte development and regeneration after injury. We determined cardiac Wt1 expression during embryonic development, in the adult, and after cardiac injury by quantitative RT-PCR and immunohistochemistry. As in vitro model, phenotypic cardiomyocyte differentiation, i.e., the appearance of rhythmically beating clones from mouse embryonic stem cells (mESCs) and associated changes in gene expression were analyzed. We detected Wt1 in cardiomyocytes from embryonic day (E10.5), the first time point investigated, until adult age. Cardiac Wt1 mRNA levels decreased during embryonic development. In the adult, Wt1 was reactivated in cardiomyocytes 48 h and 3 weeks following myocardial infarction. Wt1 mRNA levels were increased in differentiating mESCs. Overexpression of Wt1(-KTS) and Wt1(+KTS) isoforms in ES cells reduced the fraction of phenotypically cardiomyocyte differentiated clones, which was preceded by a temporary increase in c-kit expression in Wt1(-KTS) transfected ES cell clones and induction of some cardiomyocyte markers. Taken together, Wt1 shows a dynamic expression pattern during cardiomyocyte differentiation and overexpression in ES cells reduces their phenotypical cardiomyocyte differentiation.

PPARs and Myocardial Infarction.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. They are ligand-activated transcription factors and exist in three different isoforms, PPARα (NR1C1), PPARß/δ (NR1C2), and PPARγ (NR1C3). PPARs regulate a variety of functions, including glucose and lipid homeostasis, inflammation, and development. They exhibit tissue and cell type-specific expression patterns and functions. Besides the established notion of the therapeutic potential of PPAR agonists for the treatment of glucose and lipid disorders, more recent data propose specific PPAR ligands as potential therapies for cardiovascular diseases. In this review, we focus on the knowledge of PPAR function in myocardial infarction, a severe pathological condition for which therapeutic use of PPAR modulation has been suggested.

WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1.

Dysregulated alternative splicing plays a prominent role in all hallmarks of cancer. The splice factor kinase SRPK1 drives the activity of oncogenic splice factors such as SRSF1. SRSF1 in turn promotes the expression of splice isoforms that favour tumour growth, including proangiogenic VEGF. Knockdown (with siRNA) or chemical inhibition (using SPHINX) of SRPK1 in K562 leukemia and PC3 prostate cancer cell lines reduced cell proliferation, invasion and migration. In glomerular podocytes, the Wilms tumour suppressor zinc-finger transcription factor WT1 represses SRPK1 transcription. Here we show that in cancer cells WT1 activates SRPK1 transcription, unless a canonical WT1 binding site adjacent to the transcription start site is mutated. The ability of WT1 to activate SRPK1 transcription was reversed by the transcriptional corepressor BASP1, and both WT1 and BASP1 co-precipitated with the SRPK1 promoter. BASP1 significantly increased the expression of the antiangiogenic VEGF165b splice isoform. We propose that by upregulating SRPK1 transcription WT1 can direct an alternative splicing landscape that facilitates tumour growth.

The Role of PPARs in Disease.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα, PPARß/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and upon ligand binding, they modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell type-specific regulation of proliferation, differentiation, and cell survival. PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARß/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases; however, this has been limited due to the highly controversial function of PPARß/δ in cancer. This Special Issue of Cells brings together the most recent advances in understanding the various aspects of the action of PPARs, and it provides new insights into our understanding of PPARs, implying also the latest therapeutic perspectives for the utility of PPAR modulation in different disease settings.

The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis.

PPARs are ligand-activated transcriptional factors that belong to the nuclear receptor superfamily. Among them, PPAR alpha and PPAR gamma are prone to exert an antiangiogenic effect, whereas PPAR beta/delta has an opposite effect in physiological and pathological conditions. Angiogenesis has been known as a hallmark of cancer, and our recent works also demonstrate that vascular-specific PPAR beta/delta overexpression promotes tumor angiogenesis and progression in vivo. In this review, we will mainly focus on the role of PPAR beta/delta in tumor angiogenesis linked to the tumor microenvironment to further facilitate tumor progression and metastasis. Moreover, the crosstalk between PPAR beta/delta and its downstream key signal molecules involved in tumor angiogenesis will also be discussed, and the network of interplay between them will further be established in the review.

PPARs and Angiogenesis-Implications in Pathology.

Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARß/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested.