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Circulation research [journal]
- Response to letter regarding article, "embryonic stem cell-derived cardiac myocytes are not ready for human trials". [Letter]
- Circ Res 2014 Oct 24; 115(10):e30-1.
- Letter by murry et Al regarding article, "embryonic stem cell-derived cardiac myocytes are not ready for human trials". [Letter]
- Circ Res 2014 Oct 24; 115(10):e28-9.
- Oxygen: double-edged sword in cardiac function and repair. [Journal Article]
- Circ Res 2014 Oct 24; 115(10):824-5.
- Copy number variants and the genetic enigma of congenital heart disease. [Editorial]
- Circ Res 2014 Oct 24; 115(10):821-3.
- Hypoxia in plaque macrophages: a new danger signal for interleukin-1β activation? [Editorial]
- Circ Res 2014 Oct 24; 115(10):817-20.
- Stem cell in the rough: repair quotient mined out of a bone marrow niche. [Editorial]
- Circ Res 2014 Oct 24; 115(10):814-6.
- Battle of the Bulge: miR-195 Versus miR-29b in Aortic Aneurysm. [Editorial]
- Circ Res 2014 Oct 24; 115(10):812-3.
- GRK5-Mediated Exacerbation of Pathological Cardiac Hypertrophy Involves Facilitation of Nuclear NFAT Activity. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 20.
Rationale: G protein-coupled receptor (GPCR) kinases (GRKs) acting in the cardiomyocyte regulate important signaling events that control cardiac function. Both GRK2 and GRK5, the predominant GRKs expressed in the heart, have been shown to be up-regulated in failing human myocardium. While the canonical role of GRKs is to desensitize GPCRs via phosphorylation, it has been demonstrated that GRK5, unlike GRK2, can reside in the nucleus of myocytes and exert GPCR-independent effects that promote maladaptive cardiac hypertrophy and heart failure (HF). Objective: To explore novel mechanisms by which GRK5 acting in the nucleus of cardiomyocytes participates in pathological cardiac hypertrophy. Methods and Results: In this study, we have found that GRK5-mediated pathological cardiac hypertrophy involves the activation of nuclear factor of activated T-cells (NFAT) as GRK5 causes enhancement of NFAT-mediated hypertrophic gene transcription. Transgenic mice with cardiomyocyte-specific GRK5 overexpression activate an NFAT-reporter in mice basally and after hypertrophic stimuli including transverse aortic constriction (TAC) and phenylephrine treatment. Complimentary to this, GRK5 null mice exhibit less NFAT transcriptional activity after TAC. Further, loss of NFATc3 expression in the heart protected GRK5 overexpressing transgenic mice from the exaggerated hypertrophy and early progression to HF seen after TAC. Molecular studies suggest that GRK5 acts in concert with NFAT to increase hypertrophic gene transcription in the nucleus via GRK5's ability to bind DNA directly without a phosphorylation event. Conclusions: GRK5, acting in a kinase-independent manner, is a facilitator of NFAT activity and part of a DNA binding complex responsible for pathological hypertrophic gene transcription.
- Dependence of Cardiac Transverse Tubules on the BAR Domain Protein Amphiphysin II (BIN-1). [JOURNAL ARTICLE]
- Circ Res 2014 Oct 20.
Rationale: Transverse (t-) tubules regulate cardiac excitation contraction coupling and exhibit inter-chamber and inter-species differences in expression. In cardiac disease t-tubule loss occurs and affects the systolic calcium transient. However, the mechanisms controlling t-tubule maintenance and whether these factors differ between species, cardiac chambers and in a disease setting remain unclear. Objective: To determine the role of the BAR domain protein amphiphysin II (AmpII) in regulating t-tubule maintenance and the systolic calcium transient. Methods and Results: T-tubule density was assessed by di-4-ANEPPS, FM4-64 or WGA staining using confocal microscopy. In rat, ferret and sheep hearts t-tubule density and AmpII protein levels were lower in the atrium than the ventricle. Heart failure was induced in sheep using right ventricular tachypacing and ferrets by ascending aortic coarctation. In both heart failure models, AmpII protein and t-tubule density were decreased in the ventricles. In the sheep, atrial t-tubules were also lost in heart failure and AmpII levels decreased. Conversely junctophilin 2 levels did not show inter-chamber differences in the rat and ferret nor did they change in heart failure in the sheep or ferret. Αdditionally, in rat atrial and sheep heart failure atrial cells where t-tubules were absent, junctophilin 2 had sarcomeric intracellular distribution. Small interfering RNA induced knockdown of AmpII protein reduced t-tubule density, calcium transient amplitude and the synchrony of the systolic calcium transient. Conclusions: AmpII is intricately involved in t-tubule maintenance. Reducing AmpII protein decreases t-tubule density, reduces the amplitude and increases the heterogeneity of the systolic calcium transient.
- Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 20.
Rationale: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes (CMs) and left ventricular (LV) function in the heart is poorly understood. Objective: We investigated the role of Dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. Methods and Results: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in CMs at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in CMs. The lack of lysosomal translocation of mitochondrially-targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout (Drp1-CKO) mice. Following Drp1 downregulation, Drp1-CKO mice developed LV dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in Drp1-CKO mice. Although LV function in cardiac-specific Drp1 heterozygous KO (Drp1-hetCKO) mice was normal at 12 weeks of age, LV function decreased more severely after 48 hours of fasting and the infarct size/area at risk after ischemia/reperfusion (I/R) was significantly greater in Drp1-hetCKO than in control mice. Conclusions: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to I/R.