p90 ribosomal S6 kinases play a significant role in early gene regulation in the cardiomyocyte response to G(q)-protein-coupled receptor stimuli, endothelin-1 and α(1)-adrenergic receptor agonists.

ERK1/2 (extracellular-signal-regulated kinase 1/2) and their substrates RSKs (p90 ribosomal S6 kinases) phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. In the present study we investigated the role of RSKs in the transcriptomic responses to the G(q)-protein-coupled receptor agonists endothelin-1, phenylephrine (a generic α(1)-adrenergic receptor agonist) and A61603 (α(1A)-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2-3 min of stimulation (endothelin-1>A61603≈phenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased the nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of the 213 RNAs up-regulated after 1 h, 51% required RSKs for their up-regulation, whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical with, endothelin-1. As with endothelin-1, PD184352 inhibited the up-regulation of most phenylephrine-responsive transcripts, but the greater variation in the effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α(1A)-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, up-regulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to G(q)-protein-coupled receptor stimulation.

Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target.

Endothelin-1 promotes cardiomyocyte hypertrophy by inducing changes in gene expression. Immediate early genes including Atf3 (activating transcription factor 3), Egr1 (early growth response 1) and Ptgs2 (prostaglandin-endoperoxide synthase 2) are rapidly and transiently up-regulated by endothelin-1 in cardiomyocytes. Atf3 regulates the expression of downstream genes and is implicated in negative feedback regulation of other immediate early genes. To identify Atf3-regulated genes, we knocked down Atf3 expression in cardiomyocytes exposed to endothelin-1 and used microarrays to interrogate the transcriptomic effects. The expression of 23 mRNAs (including Egr1 and Ptgs2) was enhanced and the expression of 25 mRNAs was inhibited by Atf3 knockdown. Using quantitative PCR, we determined that knockdown of Atf3 had little effect on up-regulation of Egr1 mRNA over 30 min, but abolished the subsequent decline, causing sustained Egr1 mRNA expression and enhanced protein expression. This resulted from direct binding of Atf3 to the Egr1 promoter. Mathematical modelling established that Atf3 can suffice to suppress Egr1 expression. Given the widespread co-regulation of Atf3 with Egr1, we suggest that the Atf3-Egr1 negative feedback loop is of general significance. Loss of Atf3 caused abnormal cardiomyocyte growth, presumably resulting from the dysregulation of target genes. The results of the present study therefore identify Atf3 as a nexus in cardiomyocyte hypertrophy required to facilitate the full and proper growth response.

Perfusion of veins at arterial pressure increases the expression of KLF5 and cell cycle genes in smooth muscle cells.

Vascular smooth muscle cell (VSMC) proliferation remains a major cause of veno-arterial graft failure. We hypothesised that exposure of venous SMCs to arterial pressure would increase KLF5 expression and that of cell cycle genes. Porcine jugular veins were perfused at arterial or venous pressure in the absence of growth factors. The KLF5, c-myc, cyclin-D and cyclin-E expression were elevated within 24h of perfusion at arterial pressure but not at venous pressure. Arterial pressure also reduced the decline in SM-myosin heavy chain expression. These data suggest a role for KLF5 in initiating venous SMCs proliferation in response to arterial pressure.

Current status of surgery for degenerative mitral valve disease.

Degenerative mitral valve (MV) disease refers to a collection of ill-defined pathologies of the MV which manifest as mitral regurgitation (MR). Untreated MR may progress to heart failure and death. Recent advances in the surgical technique of MV repair have improved long-term surgical results to the extent that early surgery is advocated in most patients with severe MR even when asymptomatic to restore normal functional capacity and life expectancy. This article reviews the pathophysiology, evaluation, treatment, and results of surgical intervention for degenerative MR.

Ischemic mitral regurgitation: in search of the best treatment for a common condition.

Ischemic mitral regurgitation (IMR) is common after myocardial infarction. It results in a significantly increased risk of congestive heart failure and death. The assessment of these patients is challenging as IMR is a dynamic condition and varies in severity under different physiologic conditions, such as physical exertion and changes in left ventricle (LV) contractility. Assessment, therefore, includes both the mitral valve and the LV and needs to be done at rest and under conditions of stress. Treatment of IMR involves optimization of medical therapy for coronary artery disease, coronary artery revascularization, and mitral valve surgery. Most patients have mild IMR and undergo isolated coronary artery revascularization either by percutaneous coronary intervention or coronary artery bypass graft surgery (CABG). In those with severe IMR, mitral valve repair or replacement is indicated, especially if the patient is symptomatic or has impaired LV function or LV dilatation. The optimal treatment of moderate IMR is controversial; mitral valve repair at the time of CABG may be beneficial, but randomized controlled trials are needed. In selected patients with papillary muscle dyssynchrony, cardiac resynchronization therapy may also be helpful.

Tricuspid valve disease: pathophysiology and optimal management.

Tricuspid valve disease most commonly occurs secondary to left-sided heart valve disease, in particular mitral valve disease. It is a marker of adverse outcome, and patients with moderate or severe tricuspid regurgitation (TR) have a reduced survival rate. Primary TR is treated surgically if severe, and the patient is symptomatic. However, during concomitant left-sided heart valve surgery, moderate or severe secondary TR with either raised pulmonary artery pressures or tricuspid annular dilatation should also be treated. This article reviews the pathophysiology and current management of patients with tricuspid valve disease.

Rheumatic mitral valve disease: current surgical status.

Rheumatic heart disease is the most serious sequelae of rheumatic fever occurring in approximately 30% of rheumatic fever patients. Patients with acute rheumatic fever may develop varying degrees of pancarditis with associated valve disease, heart failure, and pericarditis. Worldwide, rheumatic heart disease remains a major health problem although its prevalence in the developed countries is much reduced. Involvement of the mitral valve results in mitral regurgitation and/or stenosis. Where surgery is indicated, mitral valve replacement is usually necessary although in some cases, mitral valve repair is possible.

Infective endocarditis of the mitral valve: optimal management.

Infective endocarditis continues to be associated with significant morbidity and mortality despite recent advances in its management and remains a serious and challenging condition requiring a multidisciplinary approach. Surgery is essential in at least 50% of cases. Surgical outcomes have improved with the introduction of newer techniques for valve reconstruction and also depend on many factors, including the underlying cause, causative organism, tissues involved, and host factors.