Introduction: Cardiac hypertrophy is an adaptive response to increased myocardial workload that becomes maladaptive when hypertrophied hearts are exposed to an acute metabolic stress, such as ischemia/reperfusion. Acceleration of glycolysis occurs as part of the hypertrophic response and may be maladaptive because it enhances glycolytic metabolite accumulation and proton production. Activation of AMP-activated protein kinase (AMPK), a kinase involved in the regulation of energy metabolism, is proposed as a mechanism for the acceleration of glycolysis in hypertrophied hearts. However, this concept has not yet been proven conclusively. Additionally, several studies suggest that AMPK is involved in hypertrophic remodeling of the heart by influencing cardiac myocyte growth, a suggestion that remains controversial. Hypothesis: AMPK mediates hypertrophic remodeling in response to pressure overload. Specifically, AMPK activation is a cellular signal responsible for accelerated rates of glycolysis in hypertrophied hearts. Additionally, AMPK influences myocardial structural remodeling and gene expression by limiting hypertrophic growth. Experimental Approach: To test this hypothesis, H9c2 cells, derived from embryonic rat hearts, were treated with (1 µM) arginine vasopressin (AVP) to induce hypertrophy. Substrate utilization was measured and the effects of AMPK inhibition by either Compound C or by adenovirus-mediated transfer of dominant negative AMPK were determined. Subsequently, adenovirus-mediated transfer of constitutively active form of AMPK (CA-AMPK) was expressed in H9c2 to specifically increase AMPK activity and, thereby, further characterize the role of AMPK in hypertrophic remodeling. Results: AVP induced a metabolic profile in hypertrophied H9c2 cells similar to that in intact hypertrophied hearts. Glycolysis was accelerated and palmitate oxidation was reduced with no significant alteration in glucose oxidation. These changes were associated with AMPK activation, and inhibition of AMPK ameliorated but did not normalize the hypertrophy-associated increase in glycolysis. CA-AMPK stimulated both glycolysis and fatty acid oxidation, and also increased protein synthesis and content. Howver, CA-AMPK did not induce a pathological hypertrophic phenotype as assessed by atrial natriuretic peptide expression. Conclusion: Acceleration of glycolysis in AVP-treated hypertrophied heart muscle cells is partially dependent on AMPK. AMPK is a positive regulator of cell growth in these cells, but does not induce pathological hypertrophy when acting alone.

Protein synthesis (mRNA) is tightly regulated under numerous conditions in cardiomyocytes. It can be activated by hormones such as insulin and also by other agents such as phenylephrine (PE) that activates hypertrophy in the heart. Cardiac hypertrophy involves an increase in the muscle mass of the heart, principally in the left ventricular muscle, and the increase is due to enlarged cell size, not increased cell number. A pivotal element of cardiac hypertrophy is an elevation in the rates of protein synthesis, which drives the increase in cell size causing hypertrophy. Unfortunately, we currently lack the understanding of the basic mechanisms that drives hyperactivated protein synthesis. Cardiac hypertrophy is clinically important because it is a major risk factor for heart failure. It initially serves as an adaptive response to increase cardiac output in response to higher demand, but ultimately leads to deterioration of contractility of the heart if hypertrophy is sustained. The main goal of this research project is to understand how hypertrophic agents, such as phenylephrine (PE), activate protein synthesis using adult rat ventricular cardiomyocytes as a model. Specifically, this study focuses on how the translational initiation is controlled by upstream signalling pathways.

No description available.

Protein synthesis (mRNA) is tightly regulated under numerous conditions in cardiomyocytes. It can be activated by hormones such as insulin and also by other agents such as phenylephrine (PE) that activates hypertrophy in the heart. Cardiac hypertrophy involves an increase in the muscle mass of the heart, principally in the left ventricular muscle, and the increase is due to enlarged cell size, not increased cell number. A pivotal element of cardiac hypertrophy is an elevation in the rates of protein synthesis, which drives the increase in cell size causing hypertrophy. Unfortunately, we currently lack the understanding of the basic mechanisms that drives hyperactivated protein synthesis. Cardiac hypertrophy is clinically important because it is a major risk factor for heart failure. It initially serves as an adaptive response to increase cardiac output in response to higher demand, but ultimately leads to deterioration of contractility of the heart if hypertrophy is sustained. The main goal of this research project is to understand how hypertrophic agents, such as phenylephrine (PE), activate protein synthesis using adult rat ventricular cardiomyocytes as a model. Specifically, this study focuses on how the translational initiation is controlled by upstream signalling pathways.

Left ventricular hypertrophy (LVH) in response to pressure overload is associated with increased cardiovascular morbidity and mortality, making its prevention an important therapeutic goal. The role of a calcineurin-dependent molecular pathway in the induction of pressure-overload LVH is controversial. The present study tested the hypothesis that, in the setting of LV pressure overload, activation of the systemic renin-angiotensin system was necessary for activation of this calcineurin pathway. Mild LV pressure overload was induced in male Wistar rats by abdominal aortic constriction (AAC) or transverse aortic arch constriction (TAC), producing well-matched pressure gradients of 37 ?? 8 and 35 ?? 15 mmHg, respectively. Tight transverse aortic arch constriction (TTAC) in additional animals produced a pressure gradient of 75 ?? 15 mmHg. Only AAC increased plasma renin concentration and activated the calcineurin pathway, indicated by increased nuclear NFAT3 content. Plasma renin concentration and nuclear NFAT3 content were unchanged in TAC and TTAC animals. AAC animals developed more LVH 21 days post-banding than TAC and TTAC animals: the slope of the relationship between LV/body weight ratio and systolic blood pressure was much steeper in AAC animals than the combined TAC and TTAC animals (20x10-6 versus 5x10-6, p<0.001). Treatment with the calcineurin inhibitor FK506 did not significantly alter the slope of this relationship in the combined TAC and TTAC animals (8x10-6), but FK506 abolished this relationship in AAC animals (-5x10-6, R =0.0003). These data indicate that activation of the calcineurin pathway occurs only in high-renin hypertension, providing an additional stimulus to LVH induction. Calcineurin plays no role in the induction of LVH in low-renin hypertension, which is much more common clinically.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 5 uppsatser.

The heart has the remarkable ability to adjust in response to varying stress stimuli and myocardium enlargement, referred to as cardiac hypertrophy, is a common form of stress adaptation. Divergent forms of hypertrophy can occur depending on the type and duration of the insult. The beneficial physiological form of hypertrophy is reversible and leads to improved cardiac function, while the pathological form is a maladaptive process that often transitions to heart failure. As a result of the prominence of cardiac disease, investigations into methods of reducing this detrimental form of cardiac remodeling are sought. Interestingly, pathological cardiac hypertrophy shares common features with the regulated form of cell death referred to as apoptosis. Here, we describe an essential role for apoptotic caspase-dependent signaling in the induction of pathological cardiac hypertrophy. Initially, we discovered that primary cardiomyocytes treated with hypertrophy agonists display transient activation of intrinsic-mediated apoptotic-signaling, including caspase 9 and caspase 3 activity. The necessity of functional caspase activation in hypertrophic signaling was shown by both in vitro and in vivo methods. We further investigated caspase cleavage targets histone deacetylase 3 (HDAC3) and gelsolin (GSN). HDAC3 cleavage was observed during early stages of hypertrophy and reduced in the presence of a caspase inhibitor. Caspase-mediated GSN cleavage occurred at latter stages, coincident with the cytoskeletal alterations that occur during this process. We demonstrated the requirement of GSN and its caspase-mediated processing by use of GSN expressing adenoviruses (AdVs). Use of a non-cleavable GSN-AdV provided evidence for not only the requirement of GSN in the hypertrophic response, but also for caspase mediated GSN cleavage. This body of work implicates caspase pathways and their targets as inductive signaling cues for pathological cardiac hypertrophy. These observations suggest that inhibitors that mute or suppress caspase activity and/or activity of its cognate substrates may offer novel therapeutic targets to limit the development of pathological hypertrophy.

Thesis (M.A.)--Boston University

O objetivo do estudo foi verificar os efeitos da redução parcial do treinamento de força (TF) sobre o desempenho de força dinâmica máxima (1RM), de potência e do salto vertical (SV) e sobre a área de secção transversa muscular (ASTM) dos membros superiores (MMSS) e inferiores (MMII) em indivíduos fisicamente ativos. Para isso, 33 sujeitos do sexo masculino, sem experiência em TF, foram recrutados e divididos randomicamente nos grupos: treinamento de força reduzido 1 (i.e. 2 séries x 8-6RM; 2x/semana) (TFR1), treinamento de força reduzido 2 (i.e. 4 séries x 8-6RM; 1x/semana) (TFR2) e destreinamento (DE). Inicialmente, todos efetuaram oito semanas de TF (3-4 séries, 15-6RM e 2-3x/semana). Posteriormente, os grupos TFR1 e TFR2 efetuaram oito semanas de TF com reduções no volume das sessões e/ou na frequência semanal, enquanto o grupo DE interrompeu completamente o TF. O modelo misto de análise de variância foi utilizado para testar as alterações no desempenho de 1RM, potência e SV e na ASTM de MMII e MMSS nos grupos TRF1, TFR2 e DE nas condições pré, pós-TF e pós-TFR. Ao término do período de TF, foram observados aumentos significantes de 27,9%, 26,7% e 28,4% na 1RM de MMII e de 37,2%, 38,2% e 41,8% na 1RM de MMSS nos grupos TFR1, TFR2 e DE, respectivamente. A potência de MMII aumentou 12,4%, 12,1% e 11,11%, e a de MMSS aumentou 15,8%, 15,3% e 19,3% nos grupos TFR1, TFR2 e DE, respectivamente. O salto vertical apresentou melhoras de 4,5%, 4,8% e 4,2% nos grupos TFR1, TFR2 e DE respectivamente; e a ASTM dos MMII e MMSS aumentou 6,9%, 6,1% e 5,8%; e 7,1%, 8,8% e 8,1%, respectivamente, nos grupos TFR1, TFR2 e DE. Após o período de TFR, foram observados comportamentos similares entre os grupos TFR1 e TFR2 com a manutenção dos resultados pós-TF. Por outro lado, o grupo DE apresentou quedas significantes de 17,1% e 23,5% no desempenho da 1RM e de 20,6% e 15,7% na potência de MMII e MMSS, respectivamente. O desempenho do salto vertical diminuiu em 4% e foram observadas reduções de 4,7% e 5,7% na ASTM de MMII e MMSS. Desta forma podemos concluir que um período de TFR promove manutenção no desempenho da força dinâmica máxima, da potência e do salto vertical e da massa muscular dos segmentos corporais independente do modelo de TRF utilizado / The aim of the present study was to evaluate the effect of two different reduced strength training programs on maximum dynamic strength (1RM), muscle power, and vertical jump (VJ) performance, and the maintenance of upper and lower limbs muscle mass (CSA). Thirty three young, physically active males, with no previous experience in strength training were randomly divided into three groups: reduced strength training 1 (i.e. 2 series x 8-6RM; 2x/week) (i.e. RST1), reduced strength training 2 (i.e. 4 series x 8-6RM; 1x/week) (i.e. RST2), and detraining (i.e. DE). Initially, all groups were submitted to 8 weeks of strength training (ST, 3-5 series, 15-6RM, 2-3x/week). After ST, groups RST1 and RST2 performed 8 weeks of reduced strength training, with changes in session volume and training frequency, while DE group stopped training. Mixed models analysis was used to compare 1RM, muscle power, VJ and CSA changes between groups and pre-ST, post-ST and post-RST. After 8 weeks of ST, we found significant increases of 27,9%, 26,7% and 28,4% in lower limbs 1RM and increases of 37,2%, 38,2% e 41,8% in upper limbs 1RM for RST1, RST2, and DE groups, respectively. We also found increases of 12,4%, 12,1% and 11,11% and 15,8%, 15,3% and 19,3% for lower and upper limbs power, respectively, for RST1, RST2, and DE groups. Vertical jump performance improved 4,5%, 4,8% and 4,2% for RST1, RST2, and DE groups, respectively; while lower and upper limbs CSA increased 6,9%, 6,1%, and 5,8%; and 7,1%, 8,8%, and 8,1%, respectively, for RST1, RST2, and DE groups. After the RST period, both RST1 and RST2 groups presented similar results when compared to the 8-week ST. However, the DE group showed significant decreases in lower (17,11%) and upper limbs (23,5%) 1RM; in lower (20,6%) and upper limbs (15,7%) muscle power; and in vertical jump performance (4%). Muscle cross sectional area was also reduced in lower (4,7%) and upper (5,7%) limbs after 8 weeks of DE. In conclusion, a RST period can promote maintenance of maximum dynamic strength, muscle power and vertical jump performance, and muscle mass independent of the training strategy

Introduction: Cardiac hypertrophy is an adaptive response to increased myocardial workload that becomes maladaptive when hypertrophied hearts are exposed to an acute metabolic stress, such as ischemia/reperfusion. Acceleration of glycolysis occurs as part of the hypertrophic response and may be maladaptive because it enhances glycolytic metabolite accumulation and proton production. Activation of AMP-activated protein kinase (AMPK), a kinase involved in the regulation of energy metabolism, is proposed as a mechanism for the acceleration of glycolysis in hypertrophied hearts. However, this concept has not yet been proven conclusively. Additionally, several studies suggest that AMPK is involved in hypertrophic remodeling of the heart by influencing cardiac myocyte growth, a suggestion that remains controversial. Hypothesis: AMPK mediates hypertrophic remodeling in response to pressure overload. Specifically, AMPK activation is a cellular signal responsible for accelerated rates of glycolysis in hypertrophied hearts. Additionally, AMPK influences myocardial structural remodeling and gene expression by limiting hypertrophic growth. Experimental Approach: To test this hypothesis, H9c2 cells, derived from embryonic rat hearts, were treated with (1 µM) arginine vasopressin (AVP) to induce hypertrophy. Substrate utilization was measured and the effects of AMPK inhibition by either Compound C or by adenovirus-mediated transfer of dominant negative AMPK were determined. Subsequently, adenovirus-mediated transfer of constitutively active form of AMPK (CA-AMPK) was expressed in H9c2 to specifically increase AMPK activity and, thereby, further characterize the role of AMPK in hypertrophic remodeling. Results: AVP induced a metabolic profile in hypertrophied H9c2 cells similar to that in intact hypertrophied hearts. Glycolysis was accelerated and palmitate oxidation was reduced with no significant alteration in glucose oxidation. These changes were associated with AMPK activation, and inhibition of AMPK ameliorated but did not normalize the hypertrophy-associated increase in glycolysis. CA-AMPK stimulated both glycolysis and fatty acid oxidation, and also increased protein synthesis and content. Howver, CA-AMPK did not induce a pathological hypertrophic phenotype as assessed by atrial natriuretic peptide expression. Conclusion: Acceleration of glycolysis in AVP-treated hypertrophied heart muscle cells is partially dependent on AMPK. AMPK is a positive regulator of cell growth in these cells, but does not induce pathological hypertrophy when acting alone. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate