Mechanisms for the transition from physiological to pathological cardiac hypertrophy

2020 ◽  
Vol 98 (2) ◽  
pp. 74-84 ◽  
Author(s):  
Christopher J. Oldfield ◽  
Todd A. Duhamel ◽  
Naranjan S. Dhalla
Keyword(s):  
Cardiac Hypertrophy ◽  
Contractile Function ◽  
Critical Role ◽  
Wall Stress ◽  
Capillary Density ◽  
Pathological Cardiac Hypertrophy ◽  
Hypertrophied Myocardium ◽  
Physiological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Inflammatory Processes

The heart is capable of responding to stressful situations by increasing muscle mass, which is broadly defined as cardiac hypertrophy. This phenomenon minimizes ventricular wall stress for the heart undergoing a greater than normal workload. At initial stages, cardiac hypertrophy is associated with normal or enhanced cardiac function and is considered to be adaptive or physiological; however, at later stages, if the stimulus is not removed, it is associated with contractile dysfunction and is termed as pathological cardiac hypertrophy. It is during physiological cardiac hypertrophy where the function of subcellular organelles, including the sarcolemma, sarcoplasmic reticulum, mitochondria, and myofibrils, may be upregulated, while pathological cardiac hypertrophy is associated with downregulation of these subcellular activities. The transition of physiological cardiac hypertrophy to pathological cardiac hypertrophy may be due to the reduction in blood supply to hypertrophied myocardium as a consequence of reduced capillary density. Oxidative stress, inflammatory processes, Ca2+-handling abnormalities, and apoptosis in cardiomyocytes are suggested to play a critical role in the depression of contractile function during the development of pathological hypertrophy.

Abstract 87: Endothelial Nogo-B Regulates Sphingolipid Biosynthesis to Promote the Onset of Pathological Hypertrophy During Chronic Pressure Overload

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yi Zhang ◽  
Yan Huang ◽  
Anna Cantalupo ◽  
Paula S Azevedo ◽  
Mauro Siragusa ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
De Novo ◽  
Heart Function ◽  
Critical Role ◽  
Pressure Overload ◽  
Myocardial Inflammation ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Sphingolipid Biosynthesis

Chronic pressure overload leads to an initial compensatory cardiac hypertrophy, and eventually to heart failure. The mechanisms regulating the transition from adaptive to pathological cardiac hypertrophy remain elusive. We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular functions by inhibiting the rate-limiting enzyme in de novo sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Here, we show that sphingolipids produced by the vasculature, particularly S1P, protect the heart function during pressure overload, through a paracrine mode of action. SPT activity is upregulated in banded hearts in vivo , as well as in TNF-α-activated endothelium in vitro , and loss of Nogo-mediated brake on SPT increases the production of S1P, which enhances the coronary vasculature compliance to high pressure and endothelial barrier. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B-deficient mice to wild-type levels; whereas SEW2871, an S1P 1 receptor agonist, prevents myocardial inflammation and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy, and proposes a potential new therapeutic target for the attenuation or reversal of this clinical condition.

Gene delivery of medium chain acyl-coenzyme A dehydrogenase induces physiological cardiac hypertrophy and protects against pathological remodelling

2018 ◽  
Vol 132 (3) ◽  
pp. 381-397 ◽  
Author(s):  
Bianca C. Bernardo ◽  
Kate L. Weeks ◽  
Thawin Pongsukwechkul ◽  
Xiaoming Gao ◽  
Helen Kiriazis ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Coenzyme A ◽  
Healthy Adult ◽  
Capillary Density ◽  
Medium Chain ◽  
Adult Mice ◽  
Physiological Cardiac Hypertrophy ◽  
Chain Acyl ◽  
Acyl Coenzyme A

We previously showed that medium chain acyl-coenzyme A dehydrogenase (MCAD, key regulator of fatty acid oxidation) is positively modulated in the heart by the cardioprotective kinase, phosphoinositide 3-kinase (PI3K(p110α)). Disturbances in cardiac metabolism are a feature of heart failure (HF) patients and targeting metabolic defects is considered a potential therapeutic approach. The specific role of MCAD in the adult heart is unknown. To examine the role of MCAD in the heart and to assess the therapeutic potential of increasing MCAD in the failing heart, we developed a gene therapy tool using recombinant adeno-associated viral vectors (rAAV) encoding MCAD. We hypothesised that increasing MCAD expression may recapitulate the cardioprotective properties of PI3K(p110α). rAAV6:MCAD or rAAV6:control was delivered to healthy adult mice and to mice with pre-existing pathological hypertrophy and cardiac dysfunction due to transverse aortic constriction (TAC). In healthy mice, rAAV6:MCAD induced physiological hypertrophy (increase in heart size, normal systolic function and increased capillary density). In response to TAC (~15 weeks), heart weight/tibia length increased by ~60% in control mice and ~45% in rAAV6:MCAD mice compared with sham. This was associated with an increase in cardiomyocyte cross-sectional area in both TAC groups which was similar. However, hypertrophy in TAC rAAV6:MCAD mice was associated with less fibrosis, a trend for increased capillary density and a more favourable molecular profile compared with TAC rAAV6:control mice. In summary, MCAD induced physiological cardiac hypertrophy in healthy adult mice and attenuated features of pathological remodelling in a cardiac disease model.

scholarly journals Supra-physiological dose of testosterone induces pathological cardiac hypertrophy

2016 ◽  
Vol 229 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Prapawadee Pirompol ◽  
Vassana Teekabut ◽  
Wattana Weerachatyanukul ◽  
Tepmanas Bupha-Intr ◽  
Jonggonnee Wattanapermpool
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Male Rats ◽  
Cross Sectional ◽  
Physiological Level ◽  
Testosterone Treatment ◽  
Pathological Cardiac Hypertrophy ◽  
Physiological Cardiac Hypertrophy ◽  
Hypertrophy Of The Heart ◽  
Contractile Activation

Testosterone and androgenic anabolic steroids have been misused for enhancement of physical performance despite many reports on cardiac sudden death. Although physiological level of testosterone provided many regulatory benefits to human health, including the cardiovascular function, supra-physiological levels of the hormone induce hypertrophy of the heart with unclear contractile activation. In this study, dose- and time-dependent effects of high-testosterone treatment on cardiac structure and function were evaluated. Adult male rats were divided into four groups of testosterone treatment for 0, 5, 10, and 20 mg/kg BW for 4, 8, or 12 weeks. Increases in both percentage heart:body weight ratio and cardiomyocyte cross-sectional area in representing hypertrophy of the heart were significantly shown in all testosterone-treated groups to the same degree. In 4-week-treated rats, physiological cardiac hypertrophy was apparent with an upregulation of α-MHC without any change in myofilament contractile activation. In contrast, pathological cardiac hypertrophy was observed in 8- and 12-week testosterone-treated groups, as indicated by suppression of myofilament activation and myocardial collagen deposition without transition of MHC isoforms. Only in 12-week testosterone-treated group, eccentric cardiac hypertrophy was demonstrated with unaltered myocardial stiffness, but significant reductions in the phosphorylation signals of ERK1/2 and mTOR. Results of our study suggest that the outcome of testosterone-induced cardiac hypertrophy is not dose dependent but is rather relied on the factor of exposure to duration in inducing maladaptive responses of the heart.

scholarly journals Myricetin Alleviates Pathological Cardiac Hypertrophy via TRAF6/TAK1/MAPK and Nrf2 Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hai-han Liao ◽  
Nan Zhang ◽  
Yan-yan Meng ◽  
Hong Feng ◽  
Jing-jing Yang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Mapk Signaling ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Pathological Cardiac Hypertrophy ◽  
Pathological Hypertrophy ◽  
Nrf2 Signaling Pathway

Myricetin (Myr) is a common plant-derived polyphenol and is well recognized for its multiple activities including antioxidant, anti-inflammation, anticancer, and antidiabetes. Our previous studies indicated that Myr protected mouse heart from lipopolysaccharide and streptozocin-induced injuries. However, it remained to be unclear whether Myr could prevent mouse heart from pressure overload-induced pathological hypertrophy. Wild type (WT) and cardiac Nrf2 knockdown (Nrf2-KD) mice were subjected to aortic banding (AB) surgery and then administered with Myr (200 mg/kg/d) for 6 weeks. Myr significantly alleviated AB-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction in both WT and Nrf2-KD mice. Myr also inhibited phenylephrine- (PE-) induced neonatal rat cardiomyocyte (NRCM) hypertrophy and hypertrophic markers’ expression in vitro. Mechanically, Myr markedly increased Nrf2 activity, decreased NF-κB activity, and inhibited TAK1/p38/JNK1/2 MAPK signaling in WT mouse hearts. We further demonstrated that Myr could inhibit TAK1/p38/JNK1/2 signaling via inhibiting Traf6 ubiquitination and its interaction with TAK1 after Nrf2 knockdown in NRCM. These results strongly suggested that Myr could attenuate pressure overload-induced pathological hypertrophy in vivo and PE-induced NRCM hypertrophy via enhancing Nrf2 activity and inhibiting TAK1/P38/JNK1/2 phosphorylation by regulating Traf6 ubiquitination. Thus, Myr might be a potential strategy for therapy or adjuvant therapy for malignant cardiac hypertrophy.

scholarly journals Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat

2001 ◽  
Vol 281 (6) ◽  
pp. R2029-R2036 ◽  
Author(s):  
Motoyuki Iemitsu ◽  
Takashi Miyauchi ◽  
Seiji Maeda ◽  
Satoshi Sakai ◽  
Tsutomu Kobayashi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Mrna Expression ◽  
Adrenergic Receptor ◽  
Spontaneously Hypertensive Rat ◽  
Left Ventricular ◽  
Control Group ◽  
Trained Group ◽  
Pathological Cardiac Hypertrophy ◽  
Physiological Cardiac Hypertrophy ◽  
Molecular Phenotypes

Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of β1-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of β1-adrenergic receptor kinase mRNA, which inhibits β1-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.

Abstract 427: Micrornas Have Differential Degree of Expression in Pathological Cardiac Hypertrophy Compared to Physiological Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Nidiane C Martinelli ◽  
Carolina Cohen ◽  
Daiane Silvello ◽  
Andréia Biolo ◽  
Michael Andrades ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Voluntary Exercise ◽  
Expression Levels ◽  
Time Points ◽  
Pathological Cardiac Hypertrophy ◽  
Pathway Activation ◽  
Physiological Cardiac Hypertrophy ◽  
Running Wheels ◽  
Differential Degree

Physiological and pathological left ventricular hypertrophies (LVH) are distinct processes that have differential pattern of gene expression. Based on initial stimuli, miRs expression levels can fluctuate and then cause a variance on their targets culminating in diverse cellular pathway activation. AIM: Here we compared miRs expression between pathological cardiac hypertrophy induced by transverse aortic constriction (TAC) and physiological cardiac hypertrophy induced by voluntary exercise in running wheels (EXE). METHODS: Adult male Balb/c mice (12-14 weeks old) mice were subjected to TAC or EXE protocol and data were evaluated at 7 (TAC-7D; EXE-7D) and 35 (TAC-35D; EXE-35D) days. Hypertrophy was measured by normalizing left ventricular weight to body weight (LVW/BW). We evaluated left ventricular expression levels of miRs: -26b, 27a, -143, -150, -195 and -499 by qRT-PCR in TAC and EXE groups. Comparisons between groups were performed by ANOVA with Bonferroni correction. Results are shown as mean±SEM. Results: Sedentary and Sham groups were similar among all variables tested. Animals subjected to TAC surgery demonstrated a greater hypertrophy than EXE animals at both time points (7D: 16% vs. 7%; 35D 26% vs 12%, p<0.05 for both). MiR-26b had increased levels in TAC group at both time points (7D: 1.14±0.1 vs 0.6±0.01; 35D: 4.8±1.4 vs 1.17±0.12; p<0.01 for both). We only detected an increase in miR-27a levels in TAC-7D compared to EXE-7D (2.7±1.0 vs 0.78±0.1, p <0.05). We identified an augmentation in miR-143 levels in TAC group at both time points (7D: 1.1±0.1 vs 0.75±0.1; 35D: 1.42±0.2 vs 0.9±0.1; p<0.05 for both). We detected an increase in miR-499 levels at both time points in TAC group (7D: 4.1±0.5 vs 0.67±0.2, p<0.001; 35D: 2.2±0.4 vs 0.9±0.2, p<0.01). We found an increase in miR-195 levels only in TAC-35D group compared to EXE-35D (2.6±0.3 vs 0.9±0.1, p<0.05). We did not notice any change in miR-150 levels neither at 7 days nor at 35 days. Conclusions: These preliminary data demonstrate a differential degree of miR expression between physiological and pathological hypertrophy. Further studies comparing physiological and pathological cardiac hypertrophy are necessary to find out the turning point that deviates heart from adaptive to maladaptive growth.

scholarly journals Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice

2008 ◽  
Vol 295 (3) ◽  
pp. H1303-H1310 ◽  
Author(s):  
S. Kelly Ambler ◽  
Yvonne K. Hodges ◽  
Gayle M. Jones ◽  
Carlin S. Long ◽  
Lawrence D. Horwitz
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Ventricular Remodeling ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Ribonuclease Protection Assay ◽  
Pathological Cardiac Hypertrophy ◽  
Echocardiographic Measurement ◽  
Abnormal Pattern ◽  
Ribonuclease Protection

The prolonged production of reactive oxygen species due to ischemia-reperfusion (I/R) is a potential cause of the pathological remodeling that frequently precedes heart failure. We tested the ability of a potent dithiol antioxidant, bucillamine, to protect against the long-term consequences of I/R injury in a murine model of myocardial infarction. After transiently occluding the left anterior descending coronary artery for 30 min, saline or bucillamine (10 μg/g body wt) was injected intravenously as a bolus within the first 5 min of reperfusion. The antioxidant treatment continued with daily subcutaneous injections for 4 wk. There were no differences in infarct sizes between bucillamine- and saline-treated animals. After 4 wk of reperfusion, cardiac hypertrophy was decreased by bucillamine treatment (ventricular weight-to-body weight ratios: I/R + saline, 4.5 ± 0.2 mg/g vs. I/R + bucillamine, 4.2 ± 0.1 mg/g; means ± SE; P < 0.05). Additionally, the hearts of bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32 ± 3%, versus I/R + bucillamine, 41 ± 4% ( P < 0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by ribonuclease protection assay that was consistent with pathological cardiac hypertrophy and remodeling [increased atrial natriuretic peptide, β-myosin heavy chain (MHC), skeletal α-actin; decreased sarco(endo)plasmic reticulum Ca2+ ATPase 2a, and α-MHC-to-β-MHC ratio]. These changes in gene expression were significantly attenuated by bucillamine. Therefore, treatment with a dithiol antioxidant for 4 wk after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathological cardiac remodeling.

Alterations in sarcoplasmic reticulum calcium-storing proteins in pressure-overload cardiac hypertrophy

1997 ◽  
Vol 272 (1) ◽  
pp. H168-H175 ◽  
Author(s):  
H. Tsutsui ◽  
Y. Ishibashi ◽  
K. Imanaka-Yoshida ◽  
S. Yamamoto ◽  
T. Yoshida ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Protein Level ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Regulatory Proteins ◽  
Control Value ◽  
Abdominal Aortic ◽  
Hypertrophied Myocardium

The alterations of intracellular calcium (Ca2+) homeostasis may be responsible for the contractile defects in pressure-overload cardiac hypertrophy. The Ca(2+)-adenosinetriphosphatase (ATPase) protein level of the sarcoplasmic reticulum (SR) is reduced in the hypertrophied or failing heart. However, it is not known whether Ca(2+)-storing proteins, including calsequestrin and calreticulin, are also altered during cardiac hypertrophy. We quantified SR Ca(2+)-regulatory proteins using Western blot analysis in left ventricular (LV) muscle isolated from sham-operated control rats (n = 6) and rats with pressure overload 4 wk after abdominal aortic constriction (n = 7). The contractile function of isolated LV myocytes, assessed by the sarcomere motion measured with laser diffraction, was depressed in aortic-constricted rats. The SR Ca(2+)-ATPase protein level was decreased to 56 +/- 9% (SE) of the control value in hypertrophied myocardium (P < 0.01). The calsequestrin protein level was not altered, whereas calreticulin was increased by 120 +/- 3% of the control value in aortic-constricted rats (P < 0.05). The alterations in SR Ca(2+)-regulatory proteins were equally observed in hypertrophied hearts even when the results were normalized using the amounts of myosin heavy chain proteins in each sample. Immunohistochemical staining of calsequestrin in the control heart showed cross striations at the Z lines, whereas calreticulin was hardly observed within myocytes but was intense within interstitial fibroblasts. In the hypertrophied heart, calreticulin was observed at the perinuclear region within the myocyte cytoplasm. These data indicate that pressure-overload cardiac hypertrophy causes the alterations in SR Ca(2+)-storing proteins as well as in Ca(2+)-ATPase, which may contribute to the contractile dysfunction of the hypertrophied myocytes.

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