Genetic deletion of 12/15 lipoxygenase delays vascular remodeling and limits cardiorenal dysfunction after pressure overload.

The lipid metabolizing enzyme 12/15 lipoxygenase (12/15LOX) induces proinflammatory responses that may increase cardiovascular and renal complications after cardiac insult. To define the role of 12/15LOX, 8-12-week-old male C57BL/6J wild-type (WT;  = 49) and 12/15LOX mice ( = 50) were subject to transverse aortic constriction (TAC) and monitored for 7, 28, and 56 days (d) post-TAC. Compared with WT, 12/15LOX mice experienced less left ventricle (LV) dysfunction with limited LV hypertrophy and lung edema post-TAC.

Differential requirement for DICER1 activity during the development of mitral and tricuspid valves.

Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. Here, we specifically inactivated Dicer1 in the endocardium during cardiogenesis and found that Dicer1 deletion caused congenital mitral valve stenosis and regurgitation, whereas it had no impact on other valves.

SEMA6D regulates perinatal cardiomyocyte proliferation and maturation in mice.

Cardiomyocytes undergo dramatic changes during the fetal to neonatal transition stage to adapt to the new environment. The molecular and genetic mechanisms regulating these changes remain elusive. In this study, we showed Sema6D as a novel signaling molecule regulating perinatal cardiomyocyte proliferation and maturation.

Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury.

Rationale: Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed.

Objective: We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury.

Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.

Background: c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease.

Methods: In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups.

Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart.

Background: Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling.

Cardiac progenitor cells and bone marrow-derived very small embryonic-like stem cells for cardiac repair after myocardial infarction.

Heart failure after myocardial infarction (MI) continues to be the most prevalent cause of morbidity and mortality worldwide. Although pharmaceutical agents and interventional strategies have contributed greatly to therapy, new and superior treatment modalities are urgently needed given the overall disease burden. Stem cell-based therapy is potentially a promising strategy to lead to cardiac repair after MI.

Cell therapy for ischaemic heart disease: focus on the role of resident cardiac stem cells.

Myocardial infarction results in loss of cardiomyocytes, scar formation, ventricular remodelling, and eventually heart failure. In recent years, cell therapy has emerged as a potential new strategy for patients with ischaemic heart disease. This includes embryonic and bone marrow derived stem cells.

Alpha(1)-adrenoceptor subtypes mediate negative inotropy in myocardium from alpha(1A/C)-knockout and wild type mice.

Cardiac alpha(1)-adrenoceptors (AR) have two predominant subtypes (alpha(1A)-AR and alpha(1B)-AR) however, their roles in regulating contraction are unclear. We determined the effects of stimulating alpha(1A)-AR (using the subtype-selective agonist A61603) and alpha(1B)-AR (using a gene knockout mouse lacking alpha(1A)-AR) separately, and together (using phenylephrine) on Ca(2+) transients, intracellular pH, and contraction of mouse cardiac trabeculae. Stimulation of alpha(1)-AR subtypes separately or together caused a triphasic contractile response.

Knockout of the alpha 1A/C-adrenergic receptor subtype: the alpha 1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure.

alpha 1-adrenergic receptors (ARs) play a major role in blood pressure regulation. The three alpha 1-AR subtypes (A/C, B, and D) stimulate contraction of isolated arteries, but it is uncertain how different subtypes contribute to blood pressure regulation in the intact animal. We studied the role of the alpha 1A/C subtype by using gene knockout.

LV systolic performance improves with development of hypertrophy after transverse aortic constriction in mice.

Transverse aortic constriction (TAC) is an effective technique for inducing left ventricular (LV) hypertrophy in mice. With the use of transthoracic echocardiography and Doppler measurements, we studied the effects of an acute increase in pressure overload on LV contractile performance and peak systolic wall stress index (WSI) at early time points after TAC and the time course of the development of LV hypertrophy in mice. The LV mass index was similar between TAC and sham-operated mice at postoperative day 1 but progressively increased in TAC mice by day 10.

Cloning and characterization of the mouse alpha1C/A-adrenergic receptor gene and analysis of an alpha1C promoter in cardiac myocytes: role of an MCAT element that binds transcriptional enhancer factor-1 (TEF-1).

alpha1-Adrenergic receptor (AR) subtypes in the heart are expressed by myocytes but not by fibroblasts, a feature that distinguishes alpha1-ARs from beta-ARs. Here we studied myocyte-specific expression of alpha1-ARs, focusing on the subtype alpha1C (also called alpha1A), a subtype implicated in cardiac hypertrophic signaling in rat models. We first cloned the mouse alpha1C-AR gene, which consisted of two exons with an 18 kb intron, similar to the alpha1B-AR gene.

Autonomous and growth factor-induced hypertrophy in cultured neonatal mouse cardiac myocytes. Comparison with rat.

Cultured neonatal rat cardiac myocytes have been used extensively to study cellular and molecular mechanisms of cardiac hypertrophy. However, there are only a few studies in cultured mouse myocytes despite the increasing use of genetically engineered mouse models of cardiac hypertrophy. Therefore, we characterized hypertrophic responses in low-density, serum-free cultures of neonatal mouse cardiac myocytes and compared them with rat myocytes.

Cross talk between angiotensin AT1 and alpha 1-adrenergic receptors: angiotensin II downregulates alpha 1a-adrenergic receptor subtype mRNA and density in neonatal rat cardiac myocytes.

Signaling mediated by the angiotensin (Ang) II and alpha1-adrenergic receptor (alpha1-AR) pathways is important for cardiovascular homeostasis. However, it is unknown whether Ang II has any direct effect on alpha1-AR expression and signaling in cardiac myocytes. In the present study, we determined alpha1-AR subtype mRNA levels by RNase protection; receptor density by competition binding with 5-methylurapidil; and alpha1-AR-mediated c-fos expression by Northern blot analysis.

Alpha1-adrenergic receptor subtype mRNAs are differentially regulated by alpha1-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo. Repression of alpha1B and alpha1D but induction of alpha1C.

The three cloned alpha1-adrenergic receptor (AR) subtypes, alpha1B, alpha1C, and alpha1D, can all couple to the same effector, phospholipase C, and the reason(s) for conservation of multiple subtypes remain uncertain. All three alpha1-ARs are expressed natively in cultured neonatal rat cardiac myocytes, where chronic exposure to the agonist catecholamine norepinephrine (NE) induces hypertrophic growth and gene transcription. We show here, using RNase protection, that the alpha1-AR subtype mRNAs respond in distinctly different ways during prolonged NE exposure (12 72 h).

Chronic hypoxia differentially regulates alpha 1-adrenergic receptor subtype mRNAs and inhibits alpha 1-adrenergic receptor-stimulated cardiac hypertrophy and signaling.

Background: After myocardial ischemia and/or infarction, surviving cardiac myocytes in and around the injured zone develop hypertrophy to compensate for the loss of contractile units due to myocyte injury and death. One of the factors that may be involved in the development of hypertrophy after ischemic injury is norepinephrine (NE), an agent that induces hypertrophy of cardiac myocytes through the alpha 1-adrenergic receptor (AR). It is not known, however, whether hypoxia, a major component of ischemia, has any direct effect on NE-stimulated hypertrophy.

Cloning of the rat alpha 1C-adrenergic receptor from cardiac myocytes. alpha 1C, alpha 1B, and alpha 1D mRNAs are present in cardiac myocytes but not in cardiac fibroblasts.

alpha 1-Adrenergic receptor (AR) activation in cardiac muscle has several different physiological effects that might be mediated through different alpha 1-AR subtypes. Two alpha 1-AR subtypes have been cloned from the rat, the alpha 1B and the alpha 1D; both are present in adult rat heart. A third subtype, the alpha 1C, cloned from the cow and human, was reported to be absent in the rat.

Distribution of alpha 1C-adrenergic receptor mRNA in adult rat tissues by RNase protection assay and comparison with alpha 1B and alpha 1D.

Two alpha 1-adrenergic receptor (AR) subtypes have been defined by pharmacological studies in rat tissues, the alpha 1A and the alpha 1B, whereas three alpha 1-ARs have been cloned, alpha 1B, alpha 1C, and alpha 1D. It has been reported that alpha 1C mRNA is absent in all rat tissues, making uncertain the correspondence of this cloned subtype, if any, to the native alpha 1-ARs defined by pharmacological criteria. In the present study, a partial alpha 1C-AR cDNA was obtained from rat cardiac myocytes using RT-PCR with degenerate primers.

Enzymes of ammonia assimilation in Rhizobium leguminosarum bacteroids.

The activities of the following enzymes were studied in connection with dinitrogen fixation in pea bacteroids: glutamine synthetase(L-glutamate: ammonia ligase (ADP-forming)(EC 6.3.1.