Browsing by Subject "Cardiomegaly"
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Item Athlete's Heart(1979-11-08) Blomqvist, C. GunnarItem FHL2 Inhibits Calcineurin and Represses Pathological Cardiac Hypertrophy(2010-11-02) Hojayev, Berdymammet; Hill, Joseph A.Stress-induced cardiac hypertrophy is a hallmark feature of pathological remodeling which, left unchecked, predisposes hearts to arrhythmia and failure. FHL2 is a member of the four-and-a-half LIM domain (FHL) family of proteins expressed predominantly in the heart. Targeted disruption of FHL2 leads to an exaggerated response to beta-agonist (isoproterenol)-induced cardiac hypertrophy. Isoproterenol-induced hypertrophy relies on activation of the calcineurin-NFAT pathway, and inhibition of calcineurin is sufficient to block growth in response to isoproterenol. I also observed that FHL2 is up-regulated in mouse hearts after isoproterenol treatment. Based on this, we hypothesized that FHL2 negatively regulates the calcineurin-NFAT pathway and consequently, the hypertrophic growth response. To determine whether calcineurin signaling is enhanced in the absence of FHL2, wild type (WT) and FHL2 knockout (FHL2-/-) mice were treated with isoproterenol (32 mg/kg/day). We observed a significant increase in isoproterenol-induced expression of the NFAT target genes RCAN1.4 and BNP in FHL2-/- hearts as compared to WT. To determine whether the effect of FHL2 on the abundance of NFAT target gene transcripts was mediated by calcineurin-NFAT-dependent transcription, HEK 293 cells were transfected with luciferase reporter constructs containing the NFAT-driven promoters of either RCAN1 or IL-2. Consistent with the in vivo data, knockdown of FHL2 message using siRNA led to increases in both RCAN1 and IL-2 promoter activities elicited by constitutively active calcineurin or the calcium ionophore, ionomycin. Importantly, activation of the RCAN1 promoter by ionomycin, in control and FHL2 knockdown cells, was abolished by the calcineurin inhibitor cyclosporin A, confirming the calcineurin dependence of the response. Over-expression of FHL2 in HEK 293 cells inhibited the activation of both NFAT reporters triggered by either constitutively active calcineurin or ionomycin. Furthermore, neonatal rat ventricular myocytes over-expressing FHL2 exhibited reduced hypertrophic growth in response to constitutively active calcineurin (measured by cell cross-sectional area and fetal gene expression). Finally, immunostaining of adult cardiomyocytes revealed co-localization of FHL2 and calcineurin predominantly at the sarcomere, and activation of calcineurin by endothelin-1 treatment resulted in interaction between FHL2 and calcineurin as demonstrated by coimmunoprecipitation. These observations demonstrate that FHL2 represses calcineurin-NFAT signaling and thereby suppresses hypertrophic cardiac growth at least in part by interacting with calcineurin and inhibiting its activation.Item Inhibition of Class I HDACs Blunts Cardiac Hypertrophy via TSC2-Dependent mTOR Repression(2014-11-21) Morales Medina, Cyndi Raquel; Rothermel, Beverly A.; Levine, Beth; Yin, Helen L.; Turer, Aslan T.; Hill, Joseph A.Stress-induced pathological hypertrophy is observed in most forms of heart disease. If left unchecked, pathological remodeling can lead to heart failure. Histone deacetylases (HDACs) participate in the progression of pathological cardiac growth, and small molecule inhibitors of HDACs can both reduce and regress pathological hypertrophy. The mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of cell growth. It has been shown that mTORC1 is active during cardiac hypertrophy, leading to increased protein synthesis. Inhibiting mTORC1 can repress pathological remodeling. Interestingly, pan-HDAC inhibitors target mTOR activity in some cancer models. Therefore, we hypothesized that class I HDACs regulate cardiac hypertrophy in an mTOR-dependent manner. To test this hypothesis, neonatal rat ventricular myocytes (NRVMs) were exposed to a variety of growth stimuli, and class I HDACs were inhibited by either pharmacological means or by knockdown of individual HDAC isoforms. We found that HDAC1, HDAC2 and HDAC3 act together to facilitate pathological and physiological cardiomyocyte hypertrophy. In addition, inhibition of class I HDACs decreases mTOR activation by hypertrophic growth stimuli. HDAC inhibition also decreased mTOR activity in the setting of pressure overload using an in vivo surgical model of transverse aortic constriction (TAC). Adult mice with conditional cardiomyocyte-specific knockout of both HDAC1 and HDAC2 together had improved function following TSC surgery as well as decreased mTOR activity. Tuberin (TSC2) is a component of the tuberin-hamartin complex, which inhibits mTOR. We found that inhibition of class I HDACs by either genetic knockdown or using small molecules increased expression of TSC2 in both NRVMs and embryonic stem cell-derived cardiomyocytes. Furthermore, using siRNA we observed that TSC2 is required for HDAC-dependent inhibition of mTOR in NRVMs. These findings point to mTOR, and TSC2-dependent control of mTOR, as critical components of the mechanism through which HDAC inhibitors blunt pathological cardiac growth. Together, these results enhance our understanding of the function of HDACs in cardiac pathology and facilitate the ultimate translational application of HDAC inhibitors in the treatment of heart disease.Item Pathogenesis and clinical significance of ventricular strain(1958-02-20) Chapman, Carleton B.Item RalGDS-Dependent Cardiomyocyte Autophagy Is Necessary for Load-Induced Ventricular Hypertrophy(2014-05-01) Rifki, Oktay Feridun; White, Michael A.; Hill, Joseph A.; Olson, Eric N.; Levine, BethRecent work has demonstrated that autophagy, a phylogenetically conserved, lysosome-mediated pathway of protein degradation, is a key participant in pathological cardiac remodeling. One common feature of cell growth and autophagy is membrane biogenesis and processing. The exocyst, an octomeric protein complex involved in vesicle trafficking, is implicated in numerous cellular processes, yet its role in cardiomyocyte plasticity is unknown. Here, I set out to explore the role of small G protein-dependent membrane trafficking in stress-induced cardiomyocyte remodeling and autophagy. To explore underlying mechanisms, I tested in cultured neonatal cardiomyocytes two isoforms of Ral that are downstream of RalGDS (RalA, RalB) and whose actions are mediated by the exocyst. In these experiments, mTOR inhibition was maintained in response to starvation and Torin 1 despite RalA or RalB knockdown; however, autophagy was diminished only in NRCM's with RalB knockdown, implicating RalB as required for cardiomyocyte autophagy. Hearts from mice lacking RalGDS (Ralgds-/-), a guanine exchange factor (GEF) for the Ral family of small GTPases, were similar to wild-type (WT) littermates in terms of ventricular structure, contractile performance, and gene expression. However, Ralgds-/- hearts manifested a blunted growth response (p<0.05) to TAC-mediated pressure-overload stress as determined by heart weight to body weight ratios Ventricular chamber size and contractile performance were preserved in response to TAC in Ralgds-/- mice. Interestingly, TAC-induced activation of the fetal gene program was similar in both genotypes despite the relative lack of hypertrophic growth in mutant hearts. Ralgds-/- mice also exhibited diminished load-induced cardiomyocyte autophagy. Consistent with the TAC findings, Ralgds-/- mice manifested a blunted autophagic response to 24-hour fasting, suggesting a generalized defect in autophagy. Together, these data implicate RalGDS-mediated induction of autophagy as a critical feature of load-induced cardiac hypertrophy.Item Regulation of Pyruvate Kinase M2 (PKM2) Expression and Activity in Cardiac Hypertrophy(2013-01-22) Hogen, Victor; Wang, Zhao V.; Wang, Bo; Hill, Joseph A.BACKGROUND: Cardiac hypertrophy is characterized by robust structural, metabolic, and signaling events, which include increased myocyte size and width, increased glycolytic flux, aerobic glycolysis, and induction of transcriptional programs governed by such factors as c-Myc, Fos, and Jun. We have noted that this phenotypic profile exhibits similarities to cancer, where c-Myc, HIF-1α and PKM2 contribute to tumorigenesis and enhanced cancer cell survival in the setting of oxidative stress. PKM2, highly expressed in heart, is the sole pyruvate kinase M isoform expressed in a variety of tumors and is thought to participate in shifts between anabolic and catabolic flux in glycolysis. METHODS AND RESULTS: First, we set out to determine mechanisms underlying aerobic glycolysis in cardiac hypertrophy. We hypothesized that hypertrophic growth cues, including hypoxia, mediate increases in PKM2 protein levels and oxidation at Cys-358. To test this, we first measured protein levels and activity of glycolytic PKM2 in neonatal rat ventricular myocytes maintained in culture. We evaluated four pro-growth stimuli: phenylephrine, endothelin-1, angiotensin II, and hypoxia. We observed that phenylephrine and angiotensin II did not increase normalized PKM2 protein levels, whereas hypoxia and endothelin-1 did. None of these growth stimuli increased PKM2 fractional oxidation. Further, no change in fractional oxidation of PKM2 was observed in mouse hearts subjected to one week of TAC (thoracic aortic constriction). However, an increase in total normalized PKM2 oxidation was readily detected. CONCLUSIONS: Together, these data suggest that hypoxia increases PKM2 protein levels via mechanisms mediated in part by localized ET-1 signaling. Additionally, these data suggest that TAC triggers an increase in the abundance of oxidized PKM2, mediated in part by increased PKM2 protein production. Finally, as phenylephrine did not increase PKM2 oxidation, this suggests that a non-NOX2-dependent mechanism is involved.Item [Southwestern News](1998-04-17) Stieglitz, HeatherItem [Southwestern News](2002-08-23) Carter, WayneItem [Southwestern News](2001-03-13) Shields, Amy; Hernandez, Theresa MerolaItem Ventricular hypertrophy: advantages and consequences(1989-09-21) Taylor, Anne L.