Diabetic cardiomyopathy is defined as changes in the structure and function of the myocardium that occur in diabetic patients in the absence of other cardiovascular risk factors. Our laboratory has shown that conjugated linoleic acid (CLA - a naturally-occurring polyunsaturated fatty acid with multiple health benefits) prevents endothelin-1-induced myocyte hypertrophy in vitro, as well as cardiac hypertrophy in vivo using a rodent model of spontaneously hypertensive heart failure. These cardioprotective effects of CLA were mediated through activation of peroxisome proliferator activated receptors (PPAR isomers α and γ) and stimulation of diacylglycerol kinase ζ (DGKζ). Thus, the aims of this study were to (i) determine the effect of CLA on hyperglycemia-induced structural and functional abnormalities of cardiomyocytes, and (ii) assess the role of PPAR-γ and DGK. High glucose treatment induced hypertrophy of primary adult cardiomyocytes, as indicated by augmented cell size and protein synthesis compared to untreated cardiomyocytes. The hyperglycemia-induced hypertrophy was attenuated by pretreatment with CLA (30 µM). The ability of CLA to prevent hyperglycemia-induced hypertrophy was suppressed by GW9662 (1 µM) and R59022 (10 μM), pharmacological inhibitors of PPAR-γ and DGK, respectively. In addition to structural abnormalities, high glucose impaired contractile function of adult cardiomyocytes as measured by maximal velocity of shortening, maximal velocity of relengthening, and peak shortening. Hyperglycemia-induced contractile dysfunction was likewise prevented by pretreatment with CLA (30 µM). Collectively, these findings support the idea that hyperglycemia is an independent risk factor for the development of diabetic cardiomyopathy. Hypertrophy and contractile dysfunction elicited by high glucose were prevented by CLA. The antihypertrophic actions of CLA are mediated, at least in part, by activation of PPAR-γ and DGK.

Diabetic cardiomyopathy is defined as changes in the structure and function of the myocardium that occur in diabetic patients in the absence of other cardiovascular risk factors. Our laboratory has shown that conjugated linoleic acid (CLA - a naturally-occurring polyunsaturated fatty acid with multiple health benefits) prevents endothelin-1-induced myocyte hypertrophy in vitro, as well as cardiac hypertrophy in vivo using a rodent model of spontaneously hypertensive heart failure. These cardioprotective effects of CLA were mediated through activation of peroxisome proliferator activated receptors (PPAR isomers α and γ) and stimulation of diacylglycerol kinase ζ (DGKζ). Thus, the aims of this study were to (i) determine the effect of CLA on hyperglycemia-induced structural and functional abnormalities of cardiomyocytes, and (ii) assess the role of PPAR-γ and DGK. High glucose treatment induced hypertrophy of primary adult cardiomyocytes, as indicated by augmented cell size and protein synthesis compared to untreated cardiomyocytes. The hyperglycemia-induced hypertrophy was attenuated by pretreatment with CLA (30 µM). The ability of CLA to prevent hyperglycemia-induced hypertrophy was suppressed by GW9662 (1 µM) and R59022 (10 μM), pharmacological inhibitors of PPAR-γ and DGK, respectively. In addition to structural abnormalities, high glucose impaired contractile function of adult cardiomyocytes as measured by maximal velocity of shortening, maximal velocity of relengthening, and peak shortening. Hyperglycemia-induced contractile dysfunction was likewise prevented by pretreatment with CLA (30 µM). Collectively, these findings support the idea that hyperglycemia is an independent risk factor for the development of diabetic cardiomyopathy. Hypertrophy and contractile dysfunction elicited by high glucose were prevented by CLA. The antihypertrophic actions of CLA are mediated, at least in part, by activation of PPAR-γ and DGK.

No description available.

Bone Morphogenetic Protein-7 (BMP-7) belongs to the transforming growth factor-β (TGFβ) family of cytokines has is known to have potent anti-inflammatory properties. It has been used in patients to treat osteoporosis clinically and has been reported to treat diabetic nephropathy in murine models. Moreover, studies show that inflammation is up-regulated in patients with pre-diabetes (PD). We, therefore, hypothesize that the administration of BMP-7 will attenuate inflammation in the heart of Streptozotocin (STZ)-induced PD mice. In this study, we divided C57Bl/6 mice into three groups: CONTROL, PD, and PD+BMP-7. CONTROL mice received intraperitoneal (i.p.) injections of Sodium Citrate Buffer while PD and PD+BMP-7 groups received i.p. injections of Streptozotocin (STZ) for two days. In addition, PD+BMP-7 mice received intravenous injections (i.v.) of BMP-7 (200µg/kg) on the last day of STZ injection and for the following two days. Animals were sacrificed 21 days post last injection and examined for levels of oxidative stress, inflammatory immune response, apoptosis, fibrosis and cardiac function. Our results indicate significant glucose intolerance in PD mice (p

No description available.

Au cours du couplage excitation-contraction (CEC) cardiaque, une partie du calcium (Ca2+) libéré par le réticulum sarcoplasmique (RS) via les récepteurs de la ryanodine de type (RyR2) est captée par la mitochondrie. Une fois dans la matrice mitochondriale, le Ca2+ module l’activité de plusieurs enzymes du métabolisme oxydatif ainsi que la production d’ATP. Une altération de la libération de Ca2+ du RS et une dysfonction mitochondriale ont été décrites dans plusieurs pathologies cardiovasculaires associées à des troubles métaboliques comme la cardiomyopathie diabétique (CMD). Cependant, les mécanismes qui sous-tendent le remodelage du métabolisme et de l’homéostasie calcique au stade précoce de la CMD demeurent méconnus. Afin de déterminer dans quelle mesure la dynamique calcique et le couplage excitation métabolisme oxydatif sont altérés au stade précoce de la CMD, des souris C57Bl/6 ont été soumises à un régime enrichi en graisses et en sucres (HFS) pendant deux semaines. Au terme du régime, les souris HFS présentent un hyperinsulinisme, une euglycémie et une dyslipidémie. En plus de ce statut pré-diabétique, le flux mitral (E/A) évalué par échocardiographie, est significativement diminué chez les animaux HFS par rapport aux animaux Ctrl, suggérant une dysfonction diastolique précoce du ventricule gauche. A l’échelle du cardiomyocyte, une diminution du raccourcissement cellulaire sans modification de l’amplitude des transitoires calciques induits par stimulation électrique est responsable d’une diminution de l’efficacité du CEC en condition HFS. De plus, l’entrée dynamique de Ca2+ dans la mitochondrie, évaluée à l’aide de la technique de patch-clamp en configuration cellule entière, est également significativement diminuée. Bien que l’expression du canal anionique dépendant du voltage (VDAC) et de l’unipore calcique (MCU) demeure inchangée, l’expression de la protéine MICU1 augmente. Cette altération de l’entrée de Ca2+ dans la mitochondrie est responsable d’une diminution de l’activité de la pyruvate déshydrogénase via sa phosphorylation sur le résidu ser232, réduisant ainsi l’utilisation des glucides comme substrats énergétiques. Enfin, bien que les paramètres de base de l’ECG soient comparables entre les deux groupes, les souris HFS déclenchent spontanément des troubles du rythme et présentent une altération de la modulation de la fonction cardiaque par le système nerveux autonome.Ces travaux suggèrent que MICU1, en modulant l’homéostatisie calcique, le couplage excitation-métabolisme oxydatif et la flexibilité métabolique, pourrait jouer un rôle de senseur métabolique au sein des cardiomyocytes initiant ainsi la cardiomyopathie diabétique. / During cardiac excitation-contraction coupling (ECC) a fraction of the calcium (Ca2+) released by the sarcoplasmic reticulum (SR) through type 2 Ryanodine Receptor (RyR2) is taken up by mitochondria. Once in the matrix, Ca2+ modulates several enzymes of oxidative metabolism and ATP production. SR Ca2+ release alteration and mitochondrial dysfunction have been reported in several cardiovascular diseases associated with metabolic disorders such as diabetic cardiomyopathy (DCM). However, the mechanisms that govern the metabolic remodeling and Ca2+ handling at the early stage of DCM are currently unknown. To determine whether mitochondrial Ca2+ dynamics and excitation oxidative metabolism coupling are affected at the early stage of DCM, C57Bl/6 mice were fed a standard or high fat sucrose (HFS) diet for two weeks. At the end of the diet, HFS mice display hyperinsulinemia, euglycemia and dyslipidemia. In addition to this prediabetic state, the transmitral inflow (E/A), assessed by echocardiography, is significantly reduced in HFS mice compared to their control (Ctrl) littermates suggesting an early left ventricle diastolic dysfunction. At the single cardiomyocyte level, a decrease in peak cell shortening without any change regarding the amplitude of electrically evoked Ca2+ transients leads to reduced ECC efficiency under HFS conditions. Moreover, dynamic mitochondrial Ca2+ uptake measured using the whole cell patch-clamp technique is significantly decreased. While the expression of voltage-dependent anionic channel (VDAC) and mitochondrial uniporter (MCU) is unchanged, expression of mitochondrial Ca2+ uptake protein 1 (MICU1) increases. Impaired mitochondrial Ca2+ uptake leads to reduced pyruvate dehydrogenase activity through the phosphorylation of ser232, thus decreasing the use of carbohydrates as energetic substrate. Finally, although ECG basal parameters are comparable between the two groups, HFS mice trigger spontaneous arrhythmia and impaired autonomic modulation of cardiovascular function.This study suggests that MICU1 could act as a metabolic sensor by modulating mitochondrial Ca2+ handling, excitation–oxidative metabolic coupling and the metabolic flexibility paving the way to the DCM.

Diabetic cardiomyopathy characterized by left ventricular hypertrophy predisposes diabetic and obese individuals to development of cardiac dysfunction and subsequently to heart failure. Whether hyperinsulinemia has an underlying role in development and or progression of diabetic heart disease is not well understood. We therefore studied the effects of acute hyperinsulinemia on cardiac function in euglycemic states. Acute hyperinsulinemia neither affected baseline nor inotropic response to β-adrenergic stimulation. Previous studies from our laboratory have indicated a potential role for GRK2, a serine threonine kinase in development of cardiac dysfunction in diabetic states in humans as well as in mice. To assess whether GRK2 mediates the detrimental effects of chronic hyperinsulinemia on cardiac dysfunction in mouse model of diet induced obesity, we utilized cardiomyocyte knockout of GRK2. Our results suggested lack of cardiac functional impairments in high fat fed wildtype mice, which hindered our attempts to ascertain the role of GRK2 in diabetic cardiomyopathy. Mouse models of diet induced obesity have been routinely used to study the effects of obesity and diabetes on cardiac dysfunction but recent evidence from multiple research groups has emphasized the need for evaluation of the utility and relevance of the murine diet induced obesity model for studying cardiovascular abnormalities associated with hyperinsulinemic states, including T2DM and obesity. We therefore studied the effect of chronic fat feeding (>20 weeks) alone or in combination with concomitant hypertension on cardiac function in C57BL/6J mice. Different diets were formulated with either lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat) as the source of fat and fatty acids, which contributed 60% of total calories. Insulin resistance and glucose intolerance were readily observed in mice fed a high fat diet in each of the studies. HFD resulted in the development of cardiac hypertrophy; however cardiac function as measured by B-mode echocardiography and LV catheterization was unaffected in high fat diet groups compared to their respective control diet groups. Further, dietary fat feeding regardless of the source of fat modestly altered the gene expression of a few pathological hypertrophic markers or of fibrosis related genes. However, there was an increase in expression of PPARa target genes such as Pdk4 and fatty acid metabolism genes including CD36, AcadL and Cpt1b. Cardiac mitochondrial function as assessed by oxygen consumption rates, ATP synthesis rates and reactive oxygen species production rates were unaltered in high fat diet fed mice. These results suggest that while chronic fat feeding in mice causes cardiac hypertrophy and potentially cardiometabolic remodeling, it might not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function and cause cardiac fibrosis.

No description available.

No description available.

Introdução: Ratos com diabetes induzido por estreptozotocina (STZ) apresentam alterações nos proteoglicanos Sindecan-4 e Glipican-1 no tecido cardíaco concomitantes à instalação da disfunção diastólica, evento precoce que culmina na cardiomiopatia diabética. O uso de resveratrol (RSV) em modelos animais foi capaz de melhorar a função cardíaca e o controle autonômico. Espera-se que o tratamento com esse flavonoide atue nos níveis alterados dos proteoglicanos em animais diabéticos. Objetivo: Avaliar o efeito do RSV nos parâmetros cardiovasculares e na expressão dos proteoglicanos no músculo cardíaco. Materiais e Métodos: Foram avaliados ratos Wistar machos, com doze semanas de vida, divididos em 4 grupos: controle (C, N=8); controle + RSV (CR, N=8); diabetes STZ + nicotinamida (D, N=8) e diabetes STZ + nicotinamida + RSV (DR, N=8). Foram dosados os níveis séricos de glicose, de triglicérides e foi feito o teste de resistência à insulina. Registros diretos das curvas de pressão arterial foram realizados para a análise da variabilidade da frequência cardíaca (VFC) e variabilidade da pressão arterial sistólica (VPAS) no domínio do tempo e da frequência. A sensibilidade barorreflexa foi avaliada por meio de drogas vasoativas e a função cardíaca foi avaliada por ecocardiografia de alta resolução. A localização das proteínas no tecido cardíaco foi feita por imunohistoquímica. Análise estatística utilizada: ANOVA post test Student Newman-Keuls. p < 0,05. Resultados: O peso corporal dos grupos C e CR aumentou significativamente do inicio ao final do protocolo, enquanto os grupos D e DR mantiveram seu peso inicial. A concentração de glicose sérica e dos triglicerídeos, os grupos C e CR não demonstraram diferença ao longo do protocolo, enquanto os grupos D e DR demonstraram significante aumento ao final do protocolo. Os valores de concentração de insulina, do teste de tolerância à insulina e do índice de Lee foram menores nos grupos D e DR quando comparados aos grupos C e CR. A pressão arterial sistólica foi menor nos grupos diabéticos quando comparado aos grupos controles (C e CR) o mesmo acontecendo para os valores da frequência cardíaca. A pressão arterial diastólica apresentou valores semelhantes entre os grupos C e CR e o grupo DR, somente o grupo D apresentou queda quando comparado aos outros três grupos, a pressão arterial media apresentou esse mesmo comportamento. Não foram observadas diferenças para a sensibilidade barorreflexa tanto para a resposta bradicárdica como para a resposta taquicárdica entre os grupos. Nas avaliações da VFC foi observado o aumento do Intervalo de Pulso (IP) nos grupos D e DR quando comparados aos grupos C e CR, mas foram semelhantes entre os grupos controles e diabéticos (C vs. CR e D vs. DR, respectivamente). Na VPAS os grupos D e DR apresentaram diminuição tanto no desvio padrão (DP PAS) quanto na variância (VAR PAS) quando comparados aos grupos C e CR, não houve diferença entre os grupos controles e diabéticos (C vs. CR e D vs. DR, respectivamente). A disfunção diastólica foi detectada no grupo D. A expressão das proteínas Glypican-1 e Syndecan- 4, foram significantemente maiores no grupo D quando comparada aos demais grupos e menos expressas no grupo DR quando comparada aos demais grupos. Conclusões: A administração de RSV reverteu tanto alterações morfológias como a função cardíaca global que voltou a apresentar valores muito próximos aos valores de normalidade, sem alterar as condições hemodinâmicas e autonômicas / Introduction: Streptozotocin-induced rats model show changes in proteoglycans sindecan-4 and glipican-1 in cardiac tissue concomitantly with installation of diastolic dysfunction, which is an early event that culminates in diabetic cardiomyopathy. The use of resveratrol (RSV) in animal models showed the improvement of cardiac function and autonomic control. It is expected that the treatment with this flavonoid act on altered levels of proteoglycans in diabetic rats. Objective: To evaluate the effects of resveratrol in cardiovascular parameters and the expression of proteoglycans in cardiac muscle. Material and Methods: Male Wistar rats (12 weeks old) were allocated into 4 groups: control (C, N=8), controle+RSV (CR, N=8), Diabetes STZ + nicotinamide (D, N=8) and diabetes STZ+ nicotinamide + RSV (DR, N=8). Serum levels of glucose, insulin resistance test and triglycerides were measured in order to evaluate diabetes. Arterial blood pressure records were measured in order to analyze the heart rate variability (HRV) and systolic blood pressure variabilities in frequency and time domain. The baroreflex sensivity was evaluated by vasoactive drugs infusion and the evaluation of cardiac function by high resolution echocardiography. The location of the proteins in the heart tissue was performed by immunohistochemistry. Statistics and performed analysis used: ANOVA post test Student Newman-Keuls. p < 0,05. Results: Our results showed that the body weight of groups C and CR increased significantly from the beginning to the end of the protocol, while the groups D and DR continued to have the initial weight. Regarding serum glucose concentration and triglycerides, there were no statistically significant differences between group C and CR while the group D and DR increased significantly at the end of the protocol. The values of insulin concentration, insulin tolerance test and the Lee index were lower in groups D and DR when compared to groups C and CR. The hemodynamic parameters demonstrated that systolic blood pressure was lower in diabetic groups when compared to control groups (C and CR) as well as the heart rate values. Interestingly, diastolic blood pressure showed similar values between groups C, CR and group DR. The group D decreased its diastolic blood pressure when compared to the other groups, as well as the blood pressure mean. There were no significant differences either to baroreflex sensivity, bradicardiac response and tachycardia between both groups. The evaluation of heart rate variability (HRV) showed an increase of pulse interval (PI) in groups D and DR when compared to groups C and CR. The evaluation of systolic blood pressure variability of the groups D an DR showed a decrease in both the standard deviation (SD PAS) and variance when compared to groups C and CR and there were no differences between the diabete groups and the control (C vs CR and D vs DR respectively). The diastolic disfunction was detected in group D. The Glypican-1 and Syndecan-4 protein expression were significantly higher in group D when compared to the other groups and less expressed in group DR when compared to the other groups. Conclusion: The administration of RSV reversed both morphological changes and the global cardiac function, which showed very close values to the normal range values, without changing the hemodynamic and autonomic conditions