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Circulation research [journal]
- The Long Noncoding RNA MALAT1 Regulates Endothelial Cell Function and Vessel Growth. [JOURNAL ARTICLE]
- Circ Res 2014 Mar 6.
The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long non-coding RNAs (lncRNAs) in the vasculature is largely unknown.Here, we characterized the expression of lncRNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1; also known as MALAT-1 or NEAT2).Endothelial cells of different origin express high levels of the conserved lncRNAs MALAT1, TUG1, MEG3, linc00657 and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by siRNAs or GapmeRs induced a pro-migratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by VEGF, MALAT1 siRNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hind limb ischemia. Gene expression profiling followed by confirmatory qRT-PCR demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators.Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.
- Transgenic Mice for Real Time Visualization of cGMP in Intact Adult Cardiomyocytes. [JOURNAL ARTICLE]
- Circ Res 2014 Mar 5.
cGMP is an important second messenger which regulates cardiac contractility and protects the heart from hypertrophy. However, due to the lack of real time imaging techniques, specific subcellular mechanisms and spatio-temporal dynamics of cGMP in adult cardiomyocytes are not well understood.To generate and characterize a novel cGMP sensor model to measure cGMP with nanomolar sensitivity in adult cardiomyocytes.We generated transgenic mice with cardiomyocyte-specific expression of the highly sensitive cytosolic Förster resonance energy transfer (FRET)-based cGMP biosensor red cGES-DE5 and performed the first FRET measurements of cGMP in intact adult mouse ventricular myocytes. We found very low (~10 nM) basal cytosolic cGMP levels which can be markedly increased by natriuretic peptides (CNP>ANP) and to much smaller extent by the direct stimulation of the soluble guanylyl cyclase. Constitutive activity of this cyclase contributes to basal cGMP production which is balanced by the activity of clinically established phosphodiesterase (PDE) families. The PDE3 inhibitor cilostamide showed especially strong cGMP responses. In a mild model of cardiac hypertrophy after transverse aortic constriction, PDE3 effects were not affected, while the contribution of PDE5 was significantly increased. In addition, after natriuretic peptide stimulation, PDE3 was also involved in cGMP/cAMP cross-talk.The new sensor model allows visualization of real time cGMP dynamics and pharmacology in intact adult cardiomyocytes. FRET imaging suggests the importance of well-established and potentially novel PDE-dependent mechanisms which regulate cGMP under physiological and pathophysiological conditions.
- Nitrite Therapy Improves Left Ventricular Function During Heart Failure via Restoration of Nitric Oxide (NO) Mediated Cytoprotective Signaling. [JOURNAL ARTICLE]
- Circ Res 2014 Mar 5.
Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion (MI/R) injury.No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity following pressure overload-induced hypertrophy.Serum from heart failure patients exhibited significantly decreased nitrosothiol and cGMP levels. TAC was performed in mice at 10-12 weeks of age. Sodium nitrite (50 mg/L) or saline vehicle (VEH) was administered daily in the drinking water post-operative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks post TAC to assess left ventricular dimensions and ejection fraction (LVEF). We observed increased cardiac nitrite, RXNO, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved LVEF and improved LV dimensions) at 9 weeks (p < 0.001 vs. VEH). In addition, circulating and cardiac brain natriuretic peptide (BNP) levels were attenuated in mice receiving nitrite (p < 0.05 vs. VEH). Western blot analyses revealed upregulation of Akt-eNOS-NO-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.
- PKA-Phosphorylated KV1 Channels in PSD95 Signaling Complex Contribute to the Resting Membrane Potential and Diameter of Cerebral Arteries. [JOURNAL ARTICLE]
- Circ Res 2014 Feb 28.
Postsynaptic density-95 (PSD95) is a scaffolding protein that associates with voltage-gated, Shaker-type K(+) (KV1) channels and promotes the expression of KV1 channels in vascular smooth muscle cells (cVSMCs) of the cerebral circulation. However, the physiological role of PSD95 in mediating molecular signaling in cVSMCs is unknown.We explored whether a specific interaction between PSD95 and KV1 channels enables PKA phosphorylation of KV1 channels in cVSMCs to promote vasodilation.Rat cerebral arteries (CA) were used for analyses. A membrane-permeable peptide (KV1-C peptide) corresponding to the PDZ binding motif in the C-terminus of KV1.2α was designed as a dominant negative peptide to disrupt the association of KV1 channels with PSD95. Application of KV1-C peptide to cannulated, pressurized CA rapidly induced vasoconstriction and depolarized cVSMCs. These events corresponded to reduced co-immunoprecipitation of the PSD95 and KV1 proteins without altering surface expression. Middle cerebral arterioles imaged in situ through cranial window also constricted rapidly in response to local application of KV1-C peptide. Patch-clamp recordings confirmed that KV1-C peptide attenuates KV1 channel blocker (Psora4)-sensitive current in cVSMCs. Western blots employing a phospho-PKA substrate antibody revealed CA exposed to KV1-C peptide showed markedly less phosphorylation of KV1.2α subunits. Finally, phosphatase inhibitors blunted both KV1-C peptide-mediated and PKA inhibitor peptide-mediated vasoconstriction.These findings provide initial evidence that PKA phosphorylation of KV1 channels is enabled by a dynamic association with PSD95 in CA, and suggest that a disruption of such association may compromise cerebral vasodilation and blood flow.
- Dynamic changes in myocardial matrix and relevance to disease: translational perspectives. [Journal Article]
- Circ Res 2014 Feb 28; 114(5):916-27.
The cardiac extracellular matrix (ECM) provides the architectural scaffold to support efficient contraction and relaxation of cardiomyocytes. The elegant design of the ECM facilitates optimal force transduction, electric transmission, intercellular communication, and metabolic exchange within the myocardial microenvironment. In the setting of increased wall stress, injury, or disease, the ECM can undergo a series of dynamic changes that lead to favorable chamber remodeling and functional adaptation. Over time, sustained matrix remodeling can impair diastolic and systolic function caused by excess deposition of interstitial fibrous tissue. These pathological alterations in ECM structure/function are considered central to the evolution of adverse cardiac remodeling and the development of heart failure. This review discusses the complex dynamics of the cardiac ECM in the setting of myocardial infarction, pressure overload, and volume overload. We also summarize the current status of ECM biomarkers that may have clinical value in prognosticating cardiac disease progression in patients. Finally, we discuss the most current status of drugs under evaluation for use in cardiac fibrosis.
- Molecular imaging of the cardiac extracellular matrix. [Journal Article]
- Circ Res 2014 Feb 28; 114(5):903-15.
In almost all cardiac diseases, an increase in extracellular matrix (ECM) deposition or fibrosis occurs, mostly consisting of collagen I. Whereas replacement fibrosis follows cardiomyocyte loss in myocardial infarction, reactive fibrosis is triggered by myocardial stress or inflammatory mediators and often results in ventricular stiffening, functional deterioration, and development of heart failure. Given the importance of ECM deposition in cardiac disease, ECM imaging could be a valuable clinical tool. Molecular imaging of ECM may help understand pathology, evaluate impact of novel therapy, and may eventually find a role in predicting the extent of ECM expansion and development of personalized treatment. In the current review, we provide an overview of ECM imaging including the assessment of ECM volume and molecular targeting of key players involved in ECM deposition and degradation. The targets comprise myofibroblasts, intracardiac renin-angiotensin axis, matrix metalloproteinases, and matricellular proteins.
- Matrix as an interstitial transport system. [Journal Article]
- Circ Res 2014 Feb 28; 114(5):889-902.
The extracellular matrix (ECM) is best known for its function as a structural scaffold for the tissue and more recently as a microenvironment to sequester growth factors and cytokines allowing for rapid and localized changes in their activity in the absence of new protein synthesis. In this review, we explore this and additional new aspects of ECM function in mediating cell-to-cell communications. Fibrillar and nonfibrillar components of ECM can limit and facilitate the transport of molecules through the extracellular space while also regulating interstitial hydrostatic pressure. In turn, transmembrane communications via molecules, such as ECM metalloproteinase inducer, thrombospondins, and integrins, can further mediate cell response to extracellular cues and affect ECM composition and tissue remodeling. Other means of cell-to-cell communication include extracellular microRNA transport and its contribution to gene expression in target cells and the nanotube formation between distant cells, which has recently emerged as a novel conduit for intercellular organelle sharing thereby influencing cell survival and function. The information summarized and discussed here are not limited to the cardiovascular ECM but encompass ECM in general with specific references to the cardiovascular system.
- Myocardial extracellular matrix: an ever-changing and diverse entity. [Journal Article]
- Circ Res 2014 Feb 28; 114(5):872-88.
The cardiac extracellular matrix (ECM) is a complex architectural network consisting of structural and nonstructural proteins, creating strength and plasticity. The nonstructural compartment of the ECM houses a variety of proteins, which are vital for ECM plasticity, and can be divided into 3 major groups: glycoproteins, proteoglycans, and glycosaminoglycans. The common denominator for these groups is glycosylation, which refers to the decoration of proteins or lipids with sugars. This review will discuss the fundamental role of the matrix in cardiac development, homeostasis, and remodeling, from a glycobiology point of view. Glycoproteins (eg, thrombospondins, secreted protein acidic and rich in cysteine, tenascins), proteoglycans (eg, versican, syndecans, biglycan), and glycosaminoglycans (eg, hyaluronan, heparan sulfate) are upregulated on cardiac injury and regulate key processes in the remodeling myocardium such as inflammation, fibrosis, and angiogenesis. Albeit some parallels can be made regarding the processes these proteins are involved in, their specific functions are extremely diverse. In fact, under varying conditions, individual proteins can even have opposing functions, making spatiotemporal contribution of these proteins in the rearrangement of multifaceted ECM very hard to grasp. Alterations of protein characteristics by the addition of sugars may explain the immense, yet tightly regulated, variability of the remodeling cardiac matrix. Understanding the role of glycosylation in altering the ultimate function of glycoproteins, proteoglycans, and glycosaminoglycans in the myocardium may lead to the development of new biochemical structures or compounds with great therapeutic potential for patients with heart disease.
- Translating Koch's Postulates to Identify Matrix Metalloproteinase Roles in Postmyocardial Infarction Remodeling: Cardiac Metalloproteinase Actions (CarMA) Postulates. [Journal Article]
- Circ Res 2014 Feb 28; 114(5):860-71.
The first matrix metalloproteinase (MMP) was described in 1962; and since the 1990s, cardiovascular research has focused on understanding how MMPs regulate many aspects of cardiovascular pathology from atherosclerosis formation to myocardial infarction and stroke. Although much information has been gleaned by these past reports, to a large degree MMP cardiovascular biology remains observational, with few studies homing in on cause and effect relationships. Koch's postulates were first developed in the 19th century as a way to establish microorganism function and were modified in the 20th century to include methods to establish molecular causality. In this review, we outline the concept for establishing a similar approach to determine causality in terms of MMP functions. We use left ventricular remodeling postmyocardial infarction as an example, but this approach will have broad applicability across both the cardiovascular and the MMP fields.
- The 10 most read articles published in circulation research in 2013. [Journal Article]
- Circ Res 2014 Feb 28; 114(5):765-9.