Fibroblast-specific deletion of interleukin-1 receptor-1 reduces adverse cardiac remodeling following myocardial infarction.

It has been hypothesized that interleukin-1alpha (IL-1α) is released from damaged cardiomyocytes following myocardial infarction (MI) and activates cardiac fibroblasts via its receptor (IL-1R1) to drive the early stages of cardiac remodeling. This study aimed to definitively test this hypothesis using cell type-specific IL-1α and IL-1R1 knockout (KO) mouse models. A floxed Il1α mouse was created and used to generate a cardiomyocyte-specific IL-1α KO mouse line (MIL1AKO).

TRPC5 ion channel permeation promotes weight gain in hypercholesterolaemic mice.

Transient Receptor Potential Canonical 5 (TRPC5) is a subunit of a Ca-permeable non-selective cationic channel which negatively regulates adiponectin but not leptin in mice fed chow diet. Adiponectin is a major anti-inflammatory mediator and so we hypothesized an effect of TRPC5 on the inflammatory condition of atherosclerosis. Atherosclerosis was studied in aorta of ApoE mice fed western-style diet.

Cardiomyocyte--specific expression of the nuclear matrix protein, CIZ1, stimulates production of mono-nucleated cells with an extended window of proliferation in the postnatal mouse heart.

Myocardial injury in mammals leads to heart failure through pathological cardiac remodelling that includes hypertrophy, fibrosis and ventricular dilatation. Central to this is inability of the mammalian cardiomyocyte to self-renew due to entering a quiescent state after birth. Modulation of the cardiomyocyte cell-cycle after injury is therefore a target mechanism to limit damage and potentiate repair and regeneration.

A state of reversible compensated ventricular dysfunction precedes pathological remodelling in response to cardiomyocyte-specific activity of angiotensin II type-1 receptor in mice.

Cardiac dysfunction is commonly associated with high-blood-pressure-induced cardiomyocyte hypertrophy, in response to aberrant renin-angiotensin system (RAS) activity. Ensuing pathological remodelling promotes cardiomyocyte death and cardiac fibroblast activation, leading to cardiac fibrosis. The initiating cellular mechanisms that underlie this progressive disease are poorly understood.

Piezo1 integration of vascular architecture with physiological force.

The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca(2+)-permeable non-selective cationic channels for detection of noxious mechanical impact. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology.

A differential role of macrophage TRPM2 channels in Ca²⁺ signaling and cell death in early responses to H₂O₂.

Reactive oxygen species such as H₂O₂ elevates the cytosolic Ca²⁺ concentration ([Ca²⁺]c) and causes cell death via poly(ADPR) polymerase (PARP) activation, which also represents the primary mechanism by which H₂O₂ activate the transient receptor potential melastatin-related 2 (TRPM2) channel as a Ca²⁺-permeable channel present in the plasma membrane or an intracellular Ca²⁺-release channel. The present study aimed to define the contribution and mechanisms of the TRPM2 channels in macrophage cells in mediating Ca²⁺ signaling and cell death during initial response to H₂O₂, using mouse peritoneal macrophage, RAW264.7, and differentiated THP-1 cells.

Variant Ciz1 is a circulating biomarker for early-stage lung cancer.

There is an unmet need for circulating biomarkers that can detect early-stage lung cancer. Here we show that a variant form of the nuclear matrix-associated DNA replication factor Ciz1 is present in 34/35 lung tumors but not in adjacent tissue, giving rise to stable protein quantifiable by Western blot in less than a microliter of plasma from lung cancer patients. In two independent sets, with 170 and 160 samples, respectively, variant Ciz1 correctly identified patients who had stage 1 lung cancer with clinically useful accuracy.

Constitutively active TRPC channels of adipocytes confer a mechanism for sensing dietary fatty acids and regulating adiponectin.

Rationale: Calcium entry is pivotal in the heart and blood vessels, but its significance and mechanisms in adipose tissue are largely unknown. An important factor produced by adipocytes is adiponectin, which confers myocardial protection, insulin-sensitization, and antiatherosclerotic effects.

Objective: To investigate the relevance of calcium channels to adipocytes and the production of adiponectin.

Cancer-associated variant expression and interaction of CIZ1 with cyclin A1 in differentiating male germ cells.

CIZ1 is a nuclear-matrix-associated DNA replication factor unique to higher eukaryotes, for which alternatively spliced isoforms have been associated with a range of disorders. In vitro, the CIZ1 N-terminus interacts with cyclin E and cyclin A at distinct sites, enabling functional cooperation with cyclin-A-Cdk2 to promote replication initiation. C-terminal sequences anchor CIZ1 to fixed sites on the nuclear matrix, imposing spatial constraint on cyclin-dependent kinase activity.

Ciz1 cooperates with cyclin-A-CDK2 to activate mammalian DNA replication in vitro.

Initiation of mammalian DNA replication can be reconstituted from isolated G1-phase nuclei and cell extracts, supplemented with cyclin-dependent protein kinases (CDKs). Under these conditions, cyclin E supports pre-replication complex assembly, whereas cyclin-A-associated kinase acts later to terminate assembly and activate DNA replication. The mechanism by which these events are coordinated is unknown.

H19 acts as a trans regulator of the imprinted gene network controlling growth in mice.

The imprinted H19 gene produces a non-coding RNA of unknown function. Mice lacking H19 show an overgrowth phenotype, due to a cis effect of the H19 locus on the adjacent Igf2 gene. To explore the function of the RNA itself, we produced transgenic mice overexpressing H19.

Angiotensin II type-1 receptor activation in the adult heart causes blood pressure-independent hypertrophy and cardiac dysfunction.

Aims: Sustained hypertension leads to cardiac hypertrophy that can progress, through pathological remodelling, to heart failure. Abnormality of the renin-angiotensin system (RAS) has been strongly implicated in this process. Although hypertrophy in human is an established risk factor independent of blood pressure (BP), separation of remodelling in response to local cues within the differentiated myocardium from that related to pressure overload is unresolved.

Cancer-associated missplicing of exon 4 influences the subnuclear distribution of the DNA replication factor CIZ1.

Cip1-interacting zinc finger protein 1 (CIZ1, also known as CDKN1A-interacting zinc finger protein 1) stimulates initiation of mammalian DNA replication and is normally tethered to the nuclear matrix within DNA replication foci. Here, we show that an alternatively spliced human CIZ1 variant, lacking exon 4 (Delta E4), is misexpressed as a consequence of intronic mutation in Ewing tumor (ET) cell lines. In all ET lines tested, exon 4 is skipped and an upstream mononucleotide repeat element is expanded to contain up to 28 thymidines, compared to 16 in controls.

C-terminal domains deliver the DNA replication factor Ciz1 to the nuclear matrix.

Cip1-interacting zinc finger protein 1 (Ciz1) stimulates DNA replication in vitro and is required for mammalian cells to enter S phase. Here, we show that a significant proportion of Ciz1 is retained in nuclear foci following extraction with nuclease and high salt. This suggests that Ciz1 is normally immobilized by interaction with non-chromatin nuclear structures, consistent with the nuclear matrix.

Pluripotency of reprogrammed somatic genomes in embryonic stem hybrid cells.

Somatic nuclei can be epigenetically reprogrammed by factors present in undifferentiated embryonic stem (ES) cells. The acquisition of pluripotency by somatic genomes could render such cells a viable source of personalized cell type(s) for therapeutic application, avoiding the need for controversial therapeutic cloning. To investigate this possibility, we first determined the origin of transcripts in teratomas generated from mouse (ES x somatic cell) hybrid clones.