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Circulation research [journal]
- Transient Receptor Potential Channels Contribute to Pathological Structural and Functional Remodeling After Myocardial Infarction. [JOURNAL ARTICLE]
- Circ Res 2014 Jul 21.
Rationale: The cellular and molecular basis for post myocardial infarction (MI) structural and functional remodeling is not well understood. Objective: To determine if Ca(2+) influx through transient receptor potential (canonical) (TRPC) channels contributes to post-MI structural and functional remodeling. Methods and Results: TRPC1/3/4/6 channel mRNA increased after MI in mice and was associated with TRPC-mediated Ca(2+) entry. Cardiac myocyte specific expression of a dominant negative (dn: loss of function) TRPC4 channel increased basal myocyte contractility and reduced hypertrophy and cardiac structural and functional remodeling after MI while increasing survival. We used adenovirus-mediated expression of TRPC3/4/6 channels in cultured adult feline myocytes (AFMs) to define mechanistic aspects of these TRPC-related effects. TRPC3/4/6 over expression in AFMs induced calcineurin (Cn)-Nuclear Factor of Activated T cells (NFAT) mediated hypertrophic signaling, which was reliant on caveolae targeting of TRPCs. TRPC3/4/6 expression in AFMs increased rested state contractions and increased spontaneous sarcoplasmic reticulum (SR) Ca(2+) sparks mediated by enhanced phosphorylation of the ryanodine receptor. TRPC3/4/6 expression was associated with reduced contractility and response to catecholamines during steady state pacing, likely due to enhanced SR Ca(2+) leak. Conclusions: Ca(2+) influx through TRPC channels expressed after MI activates pathological cardiac hypertrophy and reduces contractility reserve. Blocking post-MI TRPC activity improved post-MI cardiac structure and function.
- Developmental Heterogeneity of Cardiac Fibroblasts Does Not Predict Pathological Proliferation and Activation. [JOURNAL ARTICLE]
- Circ Res 2014 Jul 18.
Rationale: Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. Objective: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. Methods and Results: We showed that Thy1+CD45-CD31-CD11b-Ter119- cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using RT-PCR and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets upon injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. Conclusions: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts upon pressure overload could suggest that common signaling mechanisms stimulate their pathological response.
- Mutations in STAP1 are Associated With Autosomal Dominant Hypercholesterolemia. [JOURNAL ARTICLE]
- Circ Res 2014 Jul 17.
Rationale: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels and increased risk for coronary artery disease (CAD). ADH is caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin 9 (PCSK9). However, in a proportion of ADH cases mutations in these genes are not found. Objective: To identify a fourth locus associated with ADH. Methods and Results: Parametric linkage analysis combined with exome sequencing in a FH4 family resulted in the identification of the variant p.Glu97Asp in STAP1, encoding signal transducing adaptor family member 1. Sanger sequencing of STAP1 in 400 additional unrelated FH4 probands, in which mutations in the established LDL-associated genes were ruled out, identified a second p.Glu97Asp carrier and three additional missense variants, p.Leu69Ser, p.Ile71Thr, and p.Asp207Asn. STAP1 carriers (N=40) showed significantly higher plasma total cholesterol and LDL-c levels compared to non-affected relatives (N=91). Conclusions: We mapped a novel ADH locus at 4p13, and identified four variants in STAP1 that associate with ADH.
- Long Non-Coding RNAs in Patients With Acute Myocardial Infarction. [JOURNAL ARTICLE]
- Circ Res 2014 Jul 17.
Rationale:Long non-coding RNAs (lncRNAs) constitute a novel class of non-coding RNAs that regulate gene expression. Although recent data suggest that lncRNAs may be associated with cardiac disease, little is known about lncRNAs in the setting of myocardial ischemia. Objective: To measure lncRNAs in patients with myocardial infarction (MI). Methods and Results: We enrolled 414 patients with acute MI treated by primary percutaneous coronary intervention. Blood samples were harvested at the time of reperfusion. Expression levels of 5 lncRNAs were measured in peripheral blood cells by quantitative PCR: aHIF, ANRIL, KCNQ1OT1, MIAT and MALAT1. Levels of aHIF, KCNQ1OT1 and MALAT1 were higher in MI patients than healthy volunteers (P<0.01), and levels of ANRIL were lower in MI patients (P=0.003). Patients with ST-elevation myocardial infarction (STEMI) had lower levels of ANRIL (P<0.001), KCNQ1OT1 (P<0.001), MIAT (P<0.001) and MALAT1 (P=0.005) compared to patients with non-STEMI. Levels of ANRIL were associated with age, diabetes and hypertension. Patients presenting within 3h of chest pain onset had elevated levels of aHIF as compared to patients presenting later on. ANRIL, KCNQ1OT1, MIAT and MALAT1 were significant univariable predictors of left ventricular dysfunction as assessed by an ejection fraction ≤40% at 4-month follow-up. In multivariable and reclassification analyses, ANRIL and KCNQ1OT1 improved the prediction of left ventricular dysfunction by a model including demographic features, clinical parameters and cardiac biomarkers. Conclusions: Levels of lncRNAs in blood cells are regulated after MI and may help in prediction of outcome. This motivates further investigation of the role of lncRNAs after MI.
- Renal Denervation for the Treatment of Cardiovascular High Risk-Hypertension or Beyond? [REVIEW]
- Circ Res 2014 Jul 18; 115(3):400-409.
Hypertension imposes a major burden of morbidity and mortality and is associated with sympathetic nervous system overactivity. Renal sympathetic denervation has been shown to reduce office blood pressure, ambulatory blood pressure, and sympathetic activity in patients with resistant hypertension. Therefore, the procedure has attracted a lot of attention. Beyond blood pressure, renal denervation has been shown to improve glucose tolerance, microalbuminuria, and arrhythmias in several experimental models and, in admittedly, often uncontrolled clinical studies. It has been demonstrated to reduce myocardial hypertrophy in a blood pressure-independent and blood pressure-dependent way. The first studies on heart failure with preserved and reduced ejection fraction are ongoing. Renal sympathetic denervation holds promise for future indications in hypertension and related comorbidities and consequences, such as metabolic disease, renal failure, and heart failure. Published data in a placebo-control blinded study, however, are needed. The aim of this review is to provide a critical and comprehensive overview of heretofore generated data on renal denervation in experimental models, in human hypertension, and on early developments in new indications, which should indicate the way to powered and performed, controlled clinical studies appropriately.
- Hippo in the path to heart repair. [Editorial]
- Circ Res 2014 Jul 18; 115(3):332-4.
- Is the Therapeutic Window for Mitochondrial ROS Half-Open or Half-Closed? Mixing Mitophagic Metaphors. [Editorial]
- Circ Res 2014 Jul 18; 115(3):329-31.
- Ca2+ in the cleft: fast and fluorescent. [Editorial]
- Circ Res 2014 Jul 18; 115(3):326-8.
- AAV Vectors Expressing LDLR Gain-of-Function Variants Demonstrate Increased Efficacy in Mouse Models of Familial Hypercholesterolemia. [JOURNAL ARTICLE]
- Circ Res 2014 Jul 14.
Rationale: Familial hypercholesterolemia (FH) is a genetic disorder that arises due to loss-of-function mutations in the low-density lipoprotein receptor (LDLR) and homozygous FH (hoFH) is a candidate for gene therapy using adeno-associated viral (AAV) vectors. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL) negatively regulate LDLR protein and could dampen AAV encoded LDLR expression. Objective: We sought to create vectors expressing gain-of-function human LDLR variants that are resistant to degradation by human PCSK9 and IDOL and thereby enhance hepatic LDLR protein abundance and plasma LDL cholesterol reduction. Methods and Results: Amino acid substitutions were introduced into the coding sequence of human LDLR cDNA to reduce interaction with hPCSK9 and hIDOL. A panel of mutant hLDLRs was initially screened in vitro for escape from PCSK9. The variant hLDLR-L318D was further evaluated using a mouse model of hoFH lacking endogenous LDLR and apolipoprotein B mRNA editing enzyme, APOBEC-1 (DKO). Administration of wild type hLDLR to DKO mice, expressing hPCSK9, led to diminished LDLR activity. However, LDLR-L318D was resistant to hPCSK9 mediated degradation and effectively reduced cholesterol levels. Similarly, the LDLR-K809R\C818A construct avoided hIDOL regulation and achieved stable reductions in serum cholesterol. An AAV8.LDLR-L318D\K809R\C818A vector that carried all three amino acid substitutions conferred partial resistance to both hPCSK9 and hIDOL mediated degradation. Conclusions: Amino acid substitutions in the human LDLR confer partial resistance to PCSK9 and IDOL regulatory pathways with improved reduction in cholesterol levels and improve upon a potential gene therapeutic approach to treat homozygous FH subjects.
- Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering with GATA6 Signaling. [JOURNAL ARTICLE]
- Circ Res 2014 Jul 11.
Rationale: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain. Through interactions with other transcription factors, SHP regulates diverse biological events, including glucose metabolism in liver. However, the role of SHP in adult heart diseases has not yet been demonstrated. Objective: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy. Methods and Results: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of hypertrophy in cardiomyocytes. SHP reduced the protein amount of Gata6 and by direct physical interaction with Gata6 interfered with the binding of Gata6 to GATA binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an anti-diabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced anti-hypertrophic effect was attenuated either by SHP siRNA in cardiomyocytes or in SHP null mice. Conclusions: These results establish SHP as a novel anti-hypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced anti-hypertrophic response.