FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K

2021 ◽  
Author(s):  
Kate L. Weeks ◽  
Yow Keat Tham ◽  
Suzan G. Yildiz ◽  
Yonali Alexander ◽  
Daniel G. Donner ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Physiological Cardiac Hypertrophy ◽  
Exercise Induced ◽  
Physiological Hypertrophy ◽  
Constitutively Active

The insulin-like growth factor 1 receptor (IGF1R) and phosphoinositide 3-kinase p110a (PI3K) are critical regulators of exercise-induced physiological cardiac hypertrophy, and provide protection in experimental models of pathological remodeling and heart failure. Forkhead box class O1 (FoxO1) is a transcription factor which regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K activation in vitro, but its role in physiological hypertrophy in vivo was unknown. We generated cardiomyocyte-specific FoxO1 knockout (cKO) mice and assessed the phenotype under basal conditions and settings of physiological hypertrophy induced by 1) swim training, or 2) cardiac-specific transgenic expression of constitutively active PI3K (caPI3KTg+). Under basal conditions, male and female cKO mice displayed mild interstitial fibrosis compared with control (CON) littermates, but no other signs of cardiac pathology were present. In response to exercise training, female CON mice displayed an increase (~21%) in heart weight normalized to tibia length vs untrained mice. Exercise-induced hypertrophy was blunted in cKO mice. Exercise increased cardiac Akt phosphorylation and IGF1R expression, but was comparable between genotypes. However, differences in Foxo3a, Hsp70 and autophagy markers were identified in hearts of exercised cKO mice. Deletion of FoxO1 did not reduce cardiac hypertrophy in male or female caPI3KTg+ mice. Cardiac Akt and FoxO1 protein expression were significantly reduced in hearts of caPI3KTg+ mice, which may represent a negative feedback mechanism from chronic caPI3K, and negate any further effect of reducing FoxO1 in the cKO. In summary, FoxO1 contributes to exercise-induced hypertrophy. This has important implications when considering FoxO1 as a target for treating the diseased heart.

Abstract 1828: Dyxin/Lmcd1 Mediates Cardiac Hypertrophy Both In Vitro And In Vivo

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Derk Frank ◽  
Robert Frauen ◽  
Christiane Hanselmann ◽  
Christian Kuhn ◽  
Rainer Will ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
The Novel ◽  
Rat Cardiomyocytes ◽  
A Genome

In order to identify new molecular mediators of cardiomyocyte hypertrophy, we performed a genome wide mRNA microarray screen of biomechanically stretched neonatal rat cardiomyocytes (NRCM). We found the novel sarcomeric LIM protein Dyxin/Lmcd1 being significantly upregulated (5.6x, p<0.001). Moreover, Dyxin was also significantly induced in several mouse models of myocardial hypertrophy including aortic banding, calcineurin overexpression and angiotensin stimulation, suggesting a potential role as a mediator of cardiac hypertrophy. To further test this hypothesis, we adenovirally overexpressed Dyxin in NRCM which potently induced cellular hypertrophy (150%, p<0.001) and the hypertrophic gene program (ANF, BNP). Consistent with an induction of calcineurin signalling, the calcineurin-responsive gene Rcan1– 4 (MCIP1.4) was found significantly upregulated (3.2x, p<0.001). Conversely, knockdown of Dyxin (−75% on protein level) via miRNA completely blunted the hypertrophic response to hypertrophic stimuli, including stretch and PE (both p<0.001). Furthermore, PE-mediated activation of calcineurin signaling (Upregulation of Rcan1– 4 by 7.3x, p<0.001) was completely blocked by knockdown of Dyxin. To confirm these results in vivo, we next generated transgenic mice with cardiac-restricted overexpression of Dyxin using the α -MHC promoter. Despite normal cardiac function as assessed by echocardiography, adult transgenic mice displayed significant cardiac hypertrophy in morphometrical analyses (3.9 vs. 3.5 mg/g LV/heart weight, n=8–11, p<0.05). This finding was supplemented by a robust induction of the hypertrophic gene program including ANF (3.7-fold, n=6, p=0.01) and α -skeletal actin (2.8-fold, n=6, p<0.05). Likewise, Rcan1– 4 was found upregulated (+112%, n=5, p<0.05), Taken together, we show that the novel sarcomeric z-disc protein Dyxin/Lmcd1 is significantly upregulated in several models of cardiac hypertrophy and potently induces cardiomyocyte hypertrophy both in vitro and in vivo. Mechanistically, Lmcd1/Dyxin appears to signal through the calcineurin pathway.

scholarly journals PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2

2021 ◽  
Vol 21 (6) ◽  
pp. 451-461
Author(s):  
Wei Gu ◽  
Yutong Cheng ◽  
Su Wang ◽  
Tao Sun ◽  
Zhizhong Li
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Marker Genes ◽  
Ang Ii ◽  
Phd Finger ◽  
Finger Protein ◽  
Polycomb Protein

AbstractEpigenetic regulations essentially participate in the development of cardiomyocyte hypertrophy. PHD finger protein 19 (PHF19) is a polycomb protein that controls H3K36me3 and H3K27me3. However, the roles of PHF19 in cardiac hypertrophy remain unknown. Here in this work, we observed that PHF19 promoted cardiac hypertrophy via epigenetically targeting SIRT2. In angiotensin II (Ang II)-induced cardiomyocyte hypertrophy, adenovirus-mediated knockdown of Phf19 reduced the increase in cardiomyocyte size, repressed the expression of hypertrophic marker genes Anp and Bnp, as well as inhibited protein synthesis. By contrast, Phf19 overexpression promoted Ang II-induced cardiomyocyte hypertrophy in vitro. We also knocked down Phf19 expression in mouse hearts in vivo. The results demonstrated that Phf19 knockdown reduced Ang II-induced decline in cardiac fraction shortening and ejection fraction. Phf19 knockdown also inhibited Ang II-mediated increase in heart weight, reduced cardiomyocyte size, and repressed the expression of hypertrophic marker genes in mouse hearts. Further mechanism studies showed that PHF19 suppressed the expression of SIRT2, which contributed to the function of PHF19 during cardiomyocyte hypertrophy. PHF19 bound the promoter of SIRT2 and regulated the balance between H3K27me3 and H3K36me3 to repress the expression of SIRT2 in vitro and in vivo. In human hypertrophic hearts, the overexpression of PHF19 and downregulation of SIRT2 were observed. Of importance, PHF19 expression was positively correlated with hypertrophic marker genes ANP and BNP but negatively correlated with SIRT2 in human hypertrophic hearts. Therefore, our findings demonstrated that PHF19 promoted the development of cardiac hypertrophy via epigenetically regulating SIRT2.

Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor

2001 ◽  
Vol 280 (4) ◽  
pp. H1782-H1792 ◽  
Author(s):  
Xiaomin Zhang ◽  
Gohar Azhar ◽  
Jianyuan Chai ◽  
Pamela Sheridan ◽  
Koichiro Nagano ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Muscle ◽  
Serum Response Factor ◽  
Interstitial Fibrosis ◽  
Weight Ratio ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Response Factor ◽  
Serum Response

Serum response factor (SRF), a member of the MCM1, agamous, deficiens, SRF (MADS) family of transcriptional activators, has been implicated in the transcriptional control of a number of cardiac muscle genes, including cardiac α-actin, skeletal α-actin, α-myosin heavy chain (α-MHC), and β-MHC. To better understand the in vivo role of SRF in regulating genes responsible for maintenance of cardiac function, we sought to test the hypothesis that increased cardiac-specific SRF expression might be associated with altered cardiac morphology and function. We generated transgenic mice with cardiac-specific overexpression of the human SRF gene. The transgenic mice developed cardiomyopathy and exhibited increased heart weight-to-body weight ratio, increased heart weight, and four-chamber dilation. Histological examination revealed cardiomyocyte hypertrophy, collagen deposition, and interstitial fibrosis. SRF overexpression altered the expression of SRF-regulated genes and resulted in cardiac muscle dysfunction. Our results demonstrate that sustained overexpression of SRF, in the absence of other stimuli, is sufficient to induce cardiac change and suggest that SRF is likely to be one of the downstream effectors of the signaling pathways involved in mediating cardiac hypertrophy.

Abstract 159: Cardiac Hypertrophy and Sudden Death in a Mouse Model of STIM1 Overexpression

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sanjeewa A Goonasekera ◽  
Jop van Berlo ◽  
Adam R Burr ◽  
Robert N Correll ◽  
Allen J York ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Interstitial Fibrosis ◽  
Heart Weight ◽  
Activated T Cells ◽  
Lung Weight ◽  
Tibia Length

Background: STIM1, an ER/SR resident Ca 2+ sensing protein regulates Ca 2+ entry following internal Ca 2+ store depletion in a broad range of tissues and cell types. However their putative roles in excitable tissue such as cardiac myocytes is uncertain. Results: Here we generated a mouse model of STIM1 overexpression in cardiac and skeletal muscle. Western blot analysis suggested approximately 4-6 fold STIM1 overexpression in Tg mouse hearts compared to Ntg littermates. Immunocytochemistry carried out in ventricular myocytes revealed that STIM1 and the cardiac ryanodine receptor (RyR2) co-localize. Functionally, the amplitude of Ca 2+ entry following SR Ca 2+ depletion was 2-fold greater in myocytes isolated from STIM1 Tg mice compared to NTg littermates. Echocardiographic analysis in STIM1 Tg mice showed age dependent remodeling of the myocardium with a significant decrease in fractional shortening at 16 weeks of age (14.4.5±3.8 in STIM1 Tg vs. 36.9±1.5 in Ntg). These changes were accompanied by a significant increase in heart weight to tibia length (13.6 +/- 1.4 vs 6.5 +/- 0.24) and increased lung weight to tibia length ratio (11.6+/- 2.1 vs 8.1 +/- 0.38) in STIM1 Tg mice compared to Ntg littermates. Photometry experiments in isolated ventricular myocytes demonstrated significantly increased Ca 2+ transient amplitude with an unexpected decrease in the SR Ca 2+ load associated with STIM1 overexpression. In addition transgenic mice showed increased calcineurin-nuclear factor of activated T cells (NFAT) activation in vivo, increased CaMKII activity, interstitial fibrosis and exaggerated hypertrophy following two weeks of neuroendocrine agonist or pressure overload stimulation. Conclusion: Our observations suggest that STIM1 overexpression by itself can lead to cardiac hypertrophy and contribute to pathological cardiac remodeling and possibly sudden cardiac death. The molecular mechanisms underlying these phenomena are currently under investigation.

Prostaglandin F2 alpha induces cardiac myocyte hypertrophy in vitro and cardiac growth in vivo

1996 ◽  
Vol 271 (6) ◽  
pp. H2197-H2208 ◽  
Author(s):  
J. Lai ◽  
H. Jin ◽  
R. Yang ◽  
J. Winer ◽  
W. Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Myocyte ◽  
Ventricular Myocytes ◽  
Chronic Administration ◽  
Heart Weight ◽  
Adult Rats ◽  
Myocyte Hypertrophy ◽  
Cardiac Myocyte Hypertrophy

Several prostaglandins [prostaglandin (PG) A2, -B2, -D2, -E2, -F2 alpha, and -I2 and carbaprostacyclin] and the thromboxane analogue U-46619 were analyzed for the ability to induce hypertrophy of rat neonatal cardiac ventricular myocytes. Myocyte hypertrophy was induced specifically by PGF2 alpha. Myocytes exposed to this prostanoid in culture increased in size and protein content. The contractile fibrils within the cells became organized into parallel arrays, and the cells tended to cluster and beat spontaneously. PGF2 alpha also induced the expression of c-fos, atrial natriuretic factor (ANF), and alpha-skeletal actin in these cells. The effects of PGF2 alpha were compared with several known cardiac myocyte hypertrophy factors (phenylephrine, endothelin-1, leukemia inhibitory factor, cardiotrophin-1, and angiotensin II). PGF2 alpha was found to be intermediate in potency among the factors but induced a level of ANF production that was approximately 10-fold higher than any of the other effectors. Responsiveness to PGF2 alpha was not limited to neonatal cardiocytes. Ventricular myocytes isolated from adult rats also responded specifically to PGF2 alpha with a morphological change similar to that observed with phenylephrine and by producing ANF. In rats, chronic administration of fluprostenol, a potent agonist analogue of PGF2 alpha, resulted in a dose-dependent increase in heart weight- and ventricular weight-to-body weight ratios. The amount of PGF2 alpha extractable from the hearts of rats with cardiac hypertrophy induced by myocardial infarction was also found to be greater than that in sham-operated control rats. These results indicate that PGF2 alpha may play an important role in inducing cardiac hypertrophy.

Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis

2013 ◽  
Vol 305 (1) ◽  
pp. H124-H134 ◽  
Author(s):  
Tamás Radovits ◽  
Attila Oláh ◽  
Árpád Lux ◽  
Balázs Tamás Németh ◽  
László Hidi ◽  
...  
Keyword(s):  
Exercise Training ◽  
Cardiac Hypertrophy ◽  
Rat Model ◽  
Left Ventricular ◽  
Heart Weight ◽  
Stroke Work ◽  
Functional Changes ◽  
Exercise Induced

Long-term exercise training is associated with characteristic structural and functional changes of the myocardium, termed athlete's heart. Several research groups investigated exercise training-induced left ventricular (LV) hypertrophy in animal models; however, only sporadic data exist about detailed hemodynamics. We aimed to provide functional characterization of exercise-induced cardiac hypertrophy in a rat model using the in vivo method of LV pressure-volume (P-V) analysis. After inducing LV hypertrophy by swim training, we assessed LV morphometry by echocardiography and performed LV P-V analysis using a pressure-conductance microcatheter to investigate in vivo cardiac function. Echocardiography showed LV hypertrophy (LV mass index: 2.41 ± 0.09 vs. 2.03 ± 0.08 g/kg, P < 0.01), which was confirmed by heart weight data and histomorphometry. Invasive hemodynamic measurements showed unaltered heart rate, arterial pressure, and LV end-diastolic volume along with decreased LV end-systolic volume, thus increased stroke volume and ejection fraction (73.7 ± 0.8 vs. 64.1 ± 1.5%, P < 0.01) in trained versus untrained control rats. The P-V loop-derived sensitive, load-independent contractility indexes, such as slope of end-systolic P-V relationship or preload recruitable stroke work (77.0 ± 6.8 vs. 54.3 ± 4.8 mmHg, P = 0.01) were found to be significantly increased. The observed improvement of ventriculoarterial coupling (0.37 ± 0.02 vs. 0.65 ± 0.08, P < 0.01), along with increased LV stroke work and mechanical efficiency, reflects improved mechanoenergetics of exercise-induced cardiac hypertrophy. Despite the significant hypertrophy, we observed unaltered LV stiffness (slope of end-diastolic P-V relationship: 0.043 ± 0.007 vs. 0.040 ± 0.006 mmHg/μl) and improved LV active relaxation (τ: 10.1 ± 0.6 vs. 11.9 ± 0.2 ms, P < 0.01). According to our knowledge, this is the first study that provides characterization of functional changes and hemodynamic relations in exercise-induced cardiac hypertrophy.

Mice with Megakaryocyte-Specific Deletion of TGF-β1 Are Partially Protected From Developing Cardiac Fibrosis and Systolic Dysfunction in a Pressure Overload Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 362-362
Author(s):  
Alexander Meyer ◽  
Wei Wang ◽  
Jay L. Degen ◽  
Barry S. Coller ◽  
Jasimuddin Ahamed
Keyword(s):  
Shear Force ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Heart Weight ◽  
Tgf Β1 ◽  
Specific Deletion ◽  
Severe Fibrosis

Abstract Abstract 362 Circulating platelets contain a high concentration of the multifunctional cytokine transforming growth factor-β1 (TGF-β1) in their α-granules and release it as an inactive (latent) complex upon platelet adhesion and/or activation. We recently demonstrated that shear force can activate latent TGF-β1 in vitro, and this mechanism may contribute to the activation of TGF-β1 that we observed in vivo in the carotid arteries following injury and thrombus formation. TGF-β1 is reported to be involved in the development of cardiac fibrosis in both humans and mouse models, but the cellular source(s) of TGF-β1 and its activation mechanism in vivo have not been clearly established. To test the hypothesis that platelet TGF-β1 contributes to cardiac fibrosis, we performed comparative studies of WT mice and gene-targeted animals with a megakaryocyte-specific deletion of TGF-β1 [PF4-Cre/Tgfb1flox (Tgfb1flox)] using the transverse aortic constriction (TAC) model in male C57Bl/6 mice. Both groups also underwent sham surgery as controls. We obtained blood by percutaneous puncture of the LV under ultrasound guidance and plasma samples were prepared by immediate centrifugation at 12,000 g for 5 min. This technique consistently results in plasma TGF-β1 levels in the range of ∼1.0 ng/ml, which are below those previously reported by most investigators. Tgfb1flox mice had 45% lower levels of plasma total TGF-β1 than WT animals, with a median total TGF-β1 level in WT of 1.37 ng/ml (IQR, interquartile range, 1.2–1.6; n=45) compared to 0.76 ng/ml (IQR 0.6–0.9; n=25)] in Tgfb1flox mice (p<0.001). Heart weight/body weight ratios were 42% higher in TAC- (n=15) than in sham- (n=16) operated WT mice (p<0.001) after 4 weeks, but only 11% higher in TAC- (n=13) than sham- (n=12) operated Tgfb1flox mice (p=0.02). The heart weight/body weight ratios correlated with total TGF-β1 levels in WT mice undergoing both sham and TAC surgery (r=0.66; p<0.001), but not in Tgfb1flox mice. Cardiac fibrosis was scored 4 weeks after surgery by an expert veterinary pathologist as 0 for no fibrosis, and 1+, 2+, or 3+ for mild, moderate, and severe fibrosis, respectively. 96% (22/23) of WT mice developed interstitial fibrosis after TAC, with 65% (15/23) developing mild and 30% (7/23) developing moderate (6/23) or severe (1/23) fibrosis. In contrast, only 54% (7/13) of Tgfb1flox mice developed interstitial fibrosis, with 31% (4/13) developing mild and 15% (2/13) developing moderate fibrosis; none developed severe fibrosis (p<0.01). The Tgfb1flox mice also had significantly less perivascular fibrosis than did the WT mice, although the differences were less evident (p=0.03). Cardiac function measured by echocardiography one week after TAC surgery demonstrated that Tgfb1flox mice had better systolic function than WT mice (Table).Table:Cardiac function measurements one week after TAC surgery.WTTgfb1flox†pEF [%]41 [37–48; n=11]56 [48–65; n=11]0.03SV [μl]20 [18–21; n=11]28 [24–33; n=11]0.003FS (%)27 [23–30; n=14]32 [28–37; n=13]0.05EF: ejection fraction; SV: stroke volume; FS: fractional shortening. Data are reported as median [IQR] †Wilcoxon Rank-Sum test. Presurgery values for EF, SV, and FS were similar in WT and Tgfb1flox mice We conclude that platelet TGF-β1 contributes to the development of cardiac hypertrophy, fibrosis, and systolic dysfunction induced by a high shear, TAC model. These data have important implications for understanding TGF-β1 biology and assessing the role of TGF-β1 in murine models of human diseases. Since shear can dramatically activate TGF-β1 in vitro, it is possible that increased shear force in the TAC mice generates active TGF-β1, which may contribute to the development of cardiac hypertrophy, fibrosis, and systolic dysfunction. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

2015 ◽  
Vol 36 (4) ◽  
pp. 1597-1612 ◽  
Author(s):  
Lei Liu ◽  
Chao Wang ◽  
Dianjun Sun ◽  
Shuangquan Jiang ◽  
Hong Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Intracellular Calcium Concentration ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Sham Operation ◽  
Ang Ii

Background/Aims: Intracellular calcium concentration ([Ca2+]i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex231, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca2+]i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex231. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex231 suppressed CaSR expression and downregulated autophagy by inhibiting the Ca2+/calmodulin-dependent-protein kinase-kinase-β (CaMKKβ)- AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex231 ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex231 can become a new therapeutic agent for the treatment of cardiac hypertrophy.

scholarly journals Musa balbisiana Fruit Rich in Polyphenols Attenuates Isoproterenol-Induced Cardiac Hypertrophy in Rats via Inhibition of Inflammation and Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Sima Kumari ◽  
Parmeshwar B. Katare ◽  
R. Elancheran ◽  
Hina L. Nizami ◽  
Bugga Paramesha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Subcutaneous Administration ◽  
Cardioprotective Effect ◽  
Heart Weight ◽  
Fruit Pulp ◽  
Musa Balbisiana ◽  
And Oxidative Stress

Musa balbisiana Colla (Family: Musaceae), commonly known as banana and native to India and other parts of Asia, is very rich in nutritional value and has strong antioxidant potential. In the present study, we have developed Musa balbisiana (MB) fruit pulp powder and evaluated its cardioprotective effect in cardiac hypertrophy, which is often associated with inflammation and oxidative stress. An ultra-high-pressure liquid chromatography-mass spectrometer (UPLC-MS/MS) has been used for the detection and systematic characterization of the phenolic compounds present in Musa balbisiana fruit pulp. The cardioprotective effect of MB was evaluated in a rat model of isoproterenol- (ISO-) induced cardiac hypertrophy by subcutaneous administration of isoproterenol (5 mg/kg-1/day-1), delivered through an alzet minipump for 14 days. Oral administration of MB fruit pulp powder (200 mg/kg/day) significantly (p<0.001) decreased heart weight/tail length ratio and cardiac hypertrophy markers like ANP, BNP, β-MHC, and collagen-1 gene expression. MB also attenuated ISO-induced cardiac inflammation and oxidative stress. The in vivo data were further confirmed in vitro in H9c2 cells where the antihypertrophic and anti-inflammatory effect of the aqueous extract of MB was observed in the presence of ISO and lipopolysaccharide (LPS), respectively. This study strongly suggests that supplementation of dried Musa balbisiana fruit powder can be useful for the prevention of cardiac hypertrophy via the inhibition of inflammation and oxidative stress.

Abstract 20118: Defining the Sufficiency of Atg7 to Suppress Phenylephrine-induced Cardiac Hypertrophy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Marcus Tjeerdsma ◽  
Levi Froke ◽  
Jessica Freeling ◽  
Scott Pattison
Keyword(s):  
Body Weight ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Heart Weight ◽  
Autophagic Flux ◽  
Specific Expression ◽  
Hypertrophic Growth ◽  
Fractional Shortening

Introduction: Macroautophagy is a process of bulk protein degradation. Our prior work showed that Atg7 expression is sufficient to induce autophagic flux in vitro and in vivo . When Atg7 was co-expressed with CryAB R120G in the heart, cardiac hypertrophy was blunted in heart weight/body weight ratios and fetal gene expression markers. To determine if Atg7 expression is sufficient to limit hypertrophic growth in another model, we tested the effects of Atg7 overexpression with phenylephrine-induced hypertrophy both in vitro and in vivo . Hypothesis: Atg7 will blunt the hypertrophic effects of phenylephrine. Methods: Rat neonatal cardiomyocytes were infected with adenoviruses expressing either LacZ or Atg7 and treated with phenylephrine to induce cardiomyocytes hypertrophy. Osmotic pumps were surgically implanted into control mice and mice with cardiac-specific expression of Atg7 to infuse phenylephrine (PE) or vehicle (saline) for four weeks. Results: PE treatment significantly increased neonatal cardiomyocyte areas in LacZ-expressing cells, while Atg7-expressing cardiomyocytes showed no growth. In mice, all genotypes responded to PE treatment with significantly increased heart weight/body weight ratios and increased fiber size. However, Atg7-expressing hearts differed significantly from control hearts in normalized heart mass following PE delivery. Vehicle treated Atg7-expressing hearts had 17% smaller myofiber cross-sectional areas than those from control genotypes and had a reduced hypertrophic response to PE, relative to controls. Echocardiography showed that Atg7-expressing hearts had significantly elevated cardiac function (% fractional shortening) prior to and throughout the experiment over control hearts (33% vs. 29%). PE significantly increased fractional shortening) from 29% to 36% in control hearts, but failed to significantly elevate cardiac function in Atg7-expressing hearts further (33% vs 35%). Additional assays are underway to understand the Atg7-dependent adaptations to PE. Conclusion: Atg7 expression yields modestly smaller hearts with enhanced cardiac function which may protect them from hypertrophic stresses like phenylephrine.

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