Cardiac-specific inducible overexpression of human plasma membrane Ca ATPase 4b is cardioprotective and improves survival in mice following ischemic injury.

Heart failure (HF) is associated with reduced expression of plasma membrane Ca-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally regulated cardiac-specific overexpression of hPMCA4b in mouse models of myocardial ischemia reperfusion injury (IRI) , and HF following experimental myocardial infarction (MI) Doxycycline-regulated cardiomyocyte-specific overexpression and activity of hPMCA4b produced adaptive changes in expression levels of Ca-regulatory genes, and induced hypertrophy without significant differences in Ca transients or diastolic Ca concentrations.

Enhanced proliferation and altered calcium handling in RGS2-deficient vascular smooth muscle cells.

Context: Regulator of G-protein signaling-2 (RGS2) inhibits Gq-mediated regulation of Ca(2+) signalling in vascular smooth muscle cells (VSMC).

Objective: RGS2 knockout (RGS2KO) mice are hypertensive and show arteriolar remodeling. VSMC proliferation modulates intracellular Ca(2+) concentration [Ca(2+)]i.

Clinical relevance of DNA microarray analyses using archival formalin-fixed paraffin-embedded breast cancer specimens.

Background: The ability of gene profiling to predict treatment response and prognosis in breast cancers has been demonstrated in many studies using DNA microarray analyses on RNA from fresh frozen tumor specimens. In certain clinical and research situations, performing such analyses on archival formalin fixed paraffin-embedded (FFPE) surgical specimens would be advantageous as large libraries of such specimens with long-term follow-up data are widely available. However, FFPE tissue processing can cause fragmentation and chemical modifications of the RNA.

Peptide-mediated disruption of calmodulin-cyclin E interactions inhibits proliferation of vascular smooth muscle cells and neointima formation.

Rationale: Cell cycle progression in vascular smooth muscle cells (VSMCs) is a therapeutic target for restenosis.

Objective: Having discovered that calmodulin (CaM)-dependent cyclin E/CDK2 activity underlies Ca(2+)-sensitive G(1)-to-S phase transitions in VSMCs, we sought to explore the physiological importance of the CaM-cyclin E interaction.

Methods And Results: A peptide based on the CaM binding sequence (CBS) of cyclin E was designed to interfere with CaM-cyclin E binding.

GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.

Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat type 2 diabetes, and transient GLP-1 administration improved cardiac function in humans after acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R activation before ischemic myocardial injury remain unclear.

Research Design And Methods: We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the GLP-1R agonist liraglutide.

Region-specific patterns of vascular remodelling occur early in atherosclerosis and without loss of smooth muscle cell markers.

Background: Vascular remodelling is characterized by increased smooth muscle cell (SMC) proliferation and migration. Coincident with these events, SMC markers of differentiation are known to down-regulate in advanced stages of atherosclerosis, a process known as phenotypic modulation. However, it is not known when this first begins.

c-Myb-dependent inositol 1,4,5-trisphosphate receptor type-1 expression in vascular smooth muscle cells.

Objective: The IP3 receptor-1 (IP3R1) mediates Ca2+ signals critical to vascular smooth muscle cell (VSMC) proliferation. The cell cycle-associated transcription factor c-Myb increases Ca2+ at the G1/S transition. Here we show the mechanism through which c-Myb regulates expression of IP3R1.

Cardiac function in mice lacking the glucagon-like peptide-1 receptor.

Glucagon-like peptide-1 (GLP-1) acts via its G protein-coupled receptor (GLP-1R) to regulate blood glucose. Although the GLP-1R is widely expressed in peripheral tissues, including the heart, and exogenous GLP-1 administration increases heart rate and blood pressure in rodents, the physiological importance of GLP-1R action in the cardiovascular system remains unclear. We now show that 2-month-old mice with genetic deletion of the GLP-1R (GLP-1R(-/-)) exhibit reduced resting heart rate and elevated left ventricular (LV) end diastolic pressure compared with CD-1 wild-type controls.

Conditional expression of a dominant-negative c-Myb in vascular smooth muscle cells inhibits arterial remodeling after injury.

Inhibiting activity of the c-Myb transcription factor attenuates G1 to S phase cell cycle transitions in vascular smooth muscle cells (SMCs) in vitro. To determine the effects of arterial SMC-specific expression of a dominant-negative c-Myb molecule (Myb-Engrailed) on vascular remodeling in vivo, we performed carotid artery wire-denudation in 2 independent lines of binary transgenic mice with SM22alpha promoter-defined Doxycycline-suppressible expression of Myb-Engrailed. Adult mice with arterial SMC-specific expression of Myb-Engrailed were overtly normal in appearance and did not display any changes in cardiovascular structure or physiology.