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Circulation research [journal]
- Regulatory Polymorphisms in Human DBH Affect Peripheral Gene Expression and Sympathetic Activity. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 17.
Rationale: Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the CNS and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved. Objective: To characterize regulatory variants in DBH, effect on mRNA expression, and role in modulating sympathetic tone and disease risk. Methods and Results: Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus (LC) and adrenal gland, but also in sympathetically innervated organs (liver>lung>heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2-11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in LC and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in three separate clinical cohorts. Conclusions: We demonstrate profound effects of DBH variants on expression in two sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs.
- Interaction Between Neuronal NOS Signaling and Temperature Influences SR Ca2+ Leak: Role of Nitroso-Redox Balance. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 17.
Rationale: While nitric oxide (NO) signaling modulates cardiac function and excitation-contraction coupling, opposing results due to inconsistent experimental conditions, particularly with respect to temperature, confound the ability to elucidate NO signaling pathways. Here we show that temperature significantly modulates NO effects. Objective: Test the hypothesis that temperature profoundly impacts nitroso-redox equilibrium, thereby affecting sarcomeric reticulum (SR) Ca(2+) leak. Methods and Results: We measured SR Ca(2+) leak in cardiomyocytes from wild-type (WT), NO/redox imbalance (NOS1(-⁄-)), and hyper S-nitrosylation (GSNOR(-⁄-)) mice. In WT cardiomyocytes, SR Ca(2+) leak increased as temperature decreased from 37°C to 23°C, whereas, in NOS1(‒/‒) cells, the leak suddenly increased when the temperature surpassed 30ºC. GSNOR(‒/‒) cardiomyocytes exhibited low leak throughout the temperature range. Exogenously added NO had a biphasic effect on NOS1(‒/‒) cardiomyocytes; reducing leak at 37ºC but increasing it at sub-physiologic temperatures. Oxypurinol and Tempol diminished the leak in NOS1(-⁄-) cardiomyocytes. Cooling from 37° to 23°C increased ROS generation in WT but decreased it in NOS1(-⁄-) cardiomyocytes. Oxypurinol further reduced ROS generation. At 23°C in WT cells, leak was decreased by tetrahydrobiopterin, an essential NOS cofactor. Cooling significantly increased SR Ca(2+) content in NOS1(-⁄-) cells but had no effect in WT or GSNOR(-⁄-). Conclusions: Ca(2+) leak and temperature are normally inversely proportional, whereas NOS1 deficiency reverses this effect, increasing leak and elevating ROS production as temperature increases. Reduced denitrosylation (GSNOR deficiency) eliminates the temperature dependence of leak. Thus, temperature regulates the balance between NO and ROS which in turn has a major impact on SR Ca(2+).
- The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 16.
Mitochondrial research is experiencing a renaissance in part due to the recognition that these endosymbiotic descendants of primordial protobacteria appear to be pursuing their own biological agendas. Not only is mitochondrial metabolism required to produce most of the biochemical energy that supports their eukaryotic hosts (us), but mitochondria can actively (through apoptosis and programmed necrosis) or passively (through reactive oxygen species toxicity) drive cellular dysfunction or demise. The cellular mitochondrial collective autoregulates its population through biogenic renewal and mitophagic culling; mitochondrial fission and fusion, two components of mitochondrial dynamism, are increasingly recognized as playing central roles as orchestrators of these processes. Mitochondrial dynamism is rare in striated muscle cells, so cardiac-specific genetic manipulation of mitochondrial fission and fusion factors has proven useful for revealing non-canonical functions of mitochondrial dynamics proteins. Here, we review newly described functions of mitochondrial fusion/fission proteins in cardiac mitochondrial quality control, cell death, calcium signaling, and cardiac development. A mechanistic conceptual paradigm is proposed in which cell death and selective organelle culling are not distinct processes, but are components of a unified and integrated quality control mechanism that exerts different effects when invoked to different degrees, depending upon pathophysiological context. This offers a plausible explanation for seemingly paradoxical expression of mitochondrial dynamism and death factors in cardiomyocytes wherein mitochondrial morphometric remodeling does not normally occur and the ability to recover from cell suicide is severely limited.
- mir145 Regulates TGFBR2 Expression and Matrix Synthesis in Vascular Smooth Muscle Cells. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 16.
Rationale: MicroRNA miR145 has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined. Objective: Here, we sought to explore and define the mechanisms of miR145 function in smooth muscle cells. Methods and Results: Using a combination of cell culture assays and in vivo mouse models to modulate miR145, we characterized its downstream actions on smooth muscle phenotypes. Our results show that the miR-143/145 gene cluster is induced in smooth muscle cells by coculture with endothelial cells. Endothelial cell-induced expression of miR-143/145 is augmented by Notch signaling and accordingly expression is reduced in Notch receptor-deficient cells. Screens to identify miR145-regulated genes revealed that the TGFβ pathway has a significantly high number of putative target genes, and we show that TGFβ receptor II (TGFBR2) is a direct target of miR145. Extracellular matrix (ECM) genes that are regulated by TGFBR2 were attenuated by miR145 overexpression, and miR145 mutant mice exhibit an increase in ECM synthesis. Furthermore, activation of TGFβ signaling via angiotensin II infusion revealed a pronounced fibrotic response in the absence of miR145. Conclusions: These data demonstrate a specific role for miR145 in the regulation of matrix gene expression in smooth muscle cells, and suggest that miR145 acts to suppress TGFβ-dependent ECM accumulation and fibrosis, while promoting TGFβ-induced smooth muscle cell differentiation. Our findings offer evidence to explain how TGFβ signaling exhibits distinct downstream actions via its regulation by a specific microRNA.
- Circulating CD34+ Progenitor Cells and Risk of Mortality in a Population with Coronary Artery Disease. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 16.
Rationale: Low circulating progenitor cell (PC) numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. Objective: To investigate whether low numbers of PCs associate with a greater risk of mortality in a population at high cardiovascular risk. Methods and Results: Patients undergoing coronary angiography were recruited into two cohorts (1, n=502 and 2, n=403) over separate time periods. PCs were enumerated by flow cytometry as CD(45med+) blood mononuclear cells expressing CD34, with additional quantification of subsets co-expressing CD133, VEGFR2 and CXCR4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary endpoint of all-cause death. There was an inverse association between CD34+ and CD34+/CD133+ cell counts and risk of death in Cohort 1 (β=-0.92, p=0.043 and β=-1.64, p=0.019, respectively) that was confirmed in Cohort 2 (β=-1.25, p=0.020 and β=-1.81, p=0.015, respectively). Covariate adjusted HRs in the pooled cohort (n=905) were 3.54 (1.67-7.50) and 2.46 (1.18-5.13), respectively. CD34+/CD133+ cell counts improved risk prediction metrics beyond standard risk factors. Conclusions: Reduced circulating PC counts, identified primarily as CD34+ mononuclear cells or its subset expressing CD133 are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction and cell selection for cell based therapies.
- Alpha-Catenins Control Cardiomyocyte Proliferation by Regulating Yap Activity. [JOURNAL ARTICLE]
- Circ Res 2014 Oct 10.
Rationale: Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional co-activator Yap is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood. Objective: To investigate the role of α-catenins in the heart using cardiac-specific αE- and αT-catenin double knockout (α-cat DKO) mice. Methods and Results: We used two cardiac-specific Cre transgenes to delete both αE-catenin (Ctnna1 and αT-catenin (Ctnna3) genes either in the perinatal or in the adult heart. Perinatal depletion of α-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the α-cat DKO hearts. Fetal genes were increased in the α-cat DKO hearts indicating a less mature cardiac gene expression profile. Knockdown (KD) of α-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by KD of Yap. Finally, inactivation of α-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility following myocardial infarction. Conclusions: These studies demonstrate that α-catenins are critical regulators of Yap, a transcriptional co-activator essential for cardiomyocyte proliferation. Furthermore, we provide proof-of-concept that inhibiting α-catenins might be a useful strategy to promote myocardial regeneration following injury.
- Response to Letter Regarding Article, "AT2 Receptor Activation Induces Natriuresis and Lowers Blood Pressure". [Letter]
- Circ Res 2014 Oct 10; 115(9):e26-7.
- Angiotensin II Type 2 Receptor Effects: Lesson From a Human Model of Vascular Hyporeactivity. Letter Regarding Kemp et al. [Letter]
- Circ Res 2014 Oct 10; 115(9):e24-5.
- Joshua m. Hare: converging on cardiac regeneration. [Journal Article]
- Circ Res 2014 Oct 10; 115(9):755-8.
- The magic touch: endothelial cells muscle-up adipose. [Editorial]
- Circ Res 2014 Oct 10; 115(9):752-4.