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Cardiovascular & Hematological Agents... Jan 2009In response to an increased hemodynamic load, such as pressure or volume overload, cardiac hypertrophy ensues as an adaptive mechanism. Although hypertrophy initially... (Review)
Review
In response to an increased hemodynamic load, such as pressure or volume overload, cardiac hypertrophy ensues as an adaptive mechanism. Although hypertrophy initially maintains ventricular function, a yet undefined derailment in this process eventually leads to compromised function (decompensation) and eventually culminates in congestive heart failure (CHF). Therefore, determining the molecular signatures induced during compensatory growth is important to delineate specific mechanisms responsible for the transition into CHF. Compensatory growth involves multiple processes. At the cardiomyocyte level, one major event is increased protein turnover where enhanced protein synthesis is accompanied by increased removal of deleterious proteins. Many pathways that mediate protein turnover depend on a key molecule, mammalian target of rapamycin (mTOR). In pressure-overloaded myocardium, adrenergic receptors, growth factor receptors, and integrins are known to activate mTOR in a PI3K-dependent and/or independent manner with the involvement of specific PKC isoforms. mTOR, described as a sensor of a cell's nutrition and energy status, is uniquely positioned to activate pathways that regulate translation, cell size, and the ubiquitin-proteasome system (UPS) through rapamycin-sensitive and -insensitive signaling modules. The rapamycin-sensitive complex, known as mTOR complex 1 (mTORC1), consists of mTOR, rapamycin-sensitive adaptor protein of mTOR (Raptor) and mLST8 and promotes protein translation and cell size via molecules such as S6K1. The rapamycin-insensitive complex (mTORC2) consists of mTOR, mLST8, rapamycin-insensitive companion of mTOR (Rictor), mSin1 and Protor. mTORC2 regulates the actin cytoskeleton in addition to activating Akt (Protein kinase B) for the subsequent removal of proapoptotic factors via the UPS for cell survival. In this review, we discuss pathways and key targets of mTOR complexes that mediate growth and survival of hypertrophying cardiomyocytes and the therapeutic potential of mTOR inhibitor, rapamycin.
Topics: Adaptation, Physiological; Cardiomegaly; Cell Proliferation; Cell Survival; Humans; Myocytes, Cardiac; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 19149544
DOI: 10.2174/187152509787047603 -
Cell Death & Disease Sep 2015Pathological cardiac hypertrophy is a major risk factor associated with heart failure, a state concomitant with increased cell death. However, the mechanism governing...
Pathological cardiac hypertrophy is a major risk factor associated with heart failure, a state concomitant with increased cell death. However, the mechanism governing progression of hypertrophy to apoptosis at the single-cell level remains elusive. Here, we demonstrate annexin A6 (Anxa6), a calcium (Ca(2+))-dependent phospholipid-binding protein critically regulates the transition of chronic hypertrophied cardiomyocytes to apoptosis. Treatment of the H9c2(2-1) cardiomyocytes with hypertrophic agonists upregulates and relocalizes Anxa6 with increased cytosolic punctate appearance. Live cell imaging revealed that chronic exposure to hypertrophic agonists such as phenylephrine (PE) compromises the mitochondrial membrane potential (ΔΨm) and morphological dynamics. Such chronic hypertrophic induction also activated the caspases 9 and 3 and induced cleavage of the poly-(ADP-ribose) polymerase 1 (Parp1), which are the typical downstream events in the mitochondrial pathways of apoptosis. An increased rate of apoptosis was evident in the hypertrophied cardiomyocytes after 48-72 h of treatment with the hypertrophic agonists. Anxa6 was progressively associated with the mitochondrial fraction under chronic hypertrophic stimulation, and Anxa6 knockdown severely abrogated mitochondrial network and dynamics. Ectopically expressed Anxa6 protected the mitochondrial morphology and dynamics under PE treatment, and also increased the cellular susceptibility to apoptosis. Biochemical analysis showed that Anxa6 interacts with Parp1 and its 89 kDa cleaved product in a Ca(2+)-dependent manner through the N-terminal residues (1-28). Furthermore, expression of Anxa6(S13E), a mutant dominant negative with respect to Parp1 binding, served as an enhancer of mitochondrial dynamics, even under chronic PE treatment. Chemical inhibition of Parp1 activity released the cellular vulnerability to apoptosis in Anxa6-expressing stable cell lines, thereby shifting the equilibrium away from cell death. Taken together, the present study depicts a dual regulatory function of Anxa6 that is crucial for balancing hypertrophy with apoptosis in cardiomyocytes.
Topics: Annexin A6; Apoptosis; Cardiomegaly; Heart Failure; Myocytes, Cardiac
PubMed: 26335715
DOI: 10.1038/cddis.2015.231 -
The Turkish Journal of Pediatrics 1994A 13-year-old girl with virginal hypertrophy (bilateral extensive juvenile hypertrophy) of the breasts is presented. Her breasts began to grow rapidly after puberty and...
A 13-year-old girl with virginal hypertrophy (bilateral extensive juvenile hypertrophy) of the breasts is presented. Her breasts began to grow rapidly after puberty and reached an enormous size within a year. On examination, both breasts were greatly enlarged. Routine blood chemistry and the endocrinological investigations were normal. The computerized tomography scan of the sella was unremarkable. A bilateral reduction mammaplasty was performed, and histological analysis of the breast tissue revealed the diagnosis of virginal hypertrophy. After four months her breasts began to grow again, and a second mammaplasty was performed. After this operation, tamoxifen citrate was given to prevent recurrence for four months, and during the follow-up period of 20 months, no recurrence was noted.
Topics: Adolescent; Breast; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Hypertrophy; Mammaplasty; Recurrence; Reoperation; Tamoxifen
PubMed: 7974815
DOI: No ID Found -
Proceedings of the National Academy of... May 1979When chronically provoked to increased physiologic activity, organs increase in mass through augmented protein protein synthesis. This process of compensatory...
When chronically provoked to increased physiologic activity, organs increase in mass through augmented protein protein synthesis. This process of compensatory hypertrophy can involve cell division as well as cell growth. To test for molecules that might regulate organ size, by inducing hypertrophy, we performed a series of experiments using isolated, perfused, canine hearts in which the left ventricle was beating but performed no work. Hypertrophying hearts and kidneys as well as normal control organs were extracted and the extracts were perfused through isolated heart preparations. Before and after perfusion, RNA was extracted from fragments of the isolated hearts and translated in cell-free media containing [35S]methionine. Incorporation of methionine into protein was measured by liquid scintillation spectrometry. When perfused through normal hearts, extracts from hypertrophying heart and kidney were able to increase greatly the translational ability of RNA extracted from the normal hearts; corresponding perfusates from nonhypertrophying hearts and kidneys had no effect. Our results indicate that molecules that initiate hypertrophic organ growth are extractable, are generated by the cells of the organ under stress, and are probably similar in heart and kidney and perhaps in many other organs as well.
Topics: Animals; Cardiomegaly; Dogs; Hypertrophy; Kidney; Muscle Proteins; Protein Biosynthesis
PubMed: 156367
DOI: 10.1073/pnas.76.5.2455 -
Circulation Jan 2008Pathological cardiac hypertrophy inevitably remodels, leading to functional decompensation. Although modulation of apoptosis-regulating genes occurs in cardiac...
BACKGROUND
Pathological cardiac hypertrophy inevitably remodels, leading to functional decompensation. Although modulation of apoptosis-regulating genes occurs in cardiac hypertrophy, a causal role for programmed cardiomyocyte death in left ventricular (LV) remodeling has not been established.
METHODS AND RESULTS
We targeted the gene for proapoptotic Nix, which is transcriptionally upregulated in pressure overload and Gq-dependent hypertrophies, in the mouse germ line or specifically in cardiomyocytes (knockout [KO]) and conditionally overexpressed it in the heart (transgenic [TG]). Conditional forced Nix expression acted synergistically with the prohypertrophic Gq transgene to increase cardiomyocyte apoptosis (0.8+/-0.1% in GqTG versus 7.8+/-0.6% in GqTG+NixTG; P<0.001), causing lethal cardiomyopathy with LV dilation and depressed systolic function (percent fractional shortening, 39+/-4 versus 23+/-4; P=0.042). In the reciprocal experiment, germ-line Nix ablation significantly reduced cardiomyocyte apoptosis (4.8+/-0.2% in GqTG+NixKO versus 8.4+/-0.5% in GqTG; P=0.001), which improved percent fractional shortening (43+/-3% versus 27+/-3%; P=0.017), attenuated LV remodeling, and largely prevented lethality in the Gq peripartum model of apoptotic cardiomyopathy. Cardiac-specific (Nkx2.5-Cre) Nix KO mice subjected to transverse aortic constriction developed significantly less LV dilation by echocardiography and magnetic resonance imaging, maintained concentric remodeling, and exhibited preserved LV ejection fraction (61+/-2% in transverse aortic constriction cardiac Nix KO versus 36+/-6% in transverse aortic constriction wild-type mice; P=0.003) at 9 weeks, with reduced cardiomyocyte apoptosis at day 4 (1.70+/-0.21% versus 2.73+/-0.35%; P=0.032).
CONCLUSIONS
Nix-induced cardiomyocyte apoptosis is a major determinant of adverse remodeling in pathological hypertrophies, a finding that suggests therapeutic value for apoptosis inhibition to prevent cardiomyopathic decompensation.
Topics: Animals; Apoptosis; Fibrosis; Heart Failure; Humans; Hypertrophy; Membrane Proteins; Mice; Myocardium; Myocytes, Cardiac; Proto-Oncogene Proteins; Tumor Suppressor Proteins; Ventricular Remodeling
PubMed: 18178777
DOI: 10.1161/CIRCULATIONAHA.107.727073 -
Circulation Jan 1987During the past decade our understanding of the complex interaction between cardiac muscle and coronary vascular growth has increased substantially. Some types of... (Review)
Review
During the past decade our understanding of the complex interaction between cardiac muscle and coronary vascular growth has increased substantially. Some types of cardiac hypertrophy, for example, left ventricular hypertrophy secondary to hyperthyroidism, are associated with increased coronary vascular growth. However, in most animal preparations of hypertrophy and in several clinical types of hypertrophy of the left and/or right ventricles, pathologic cardiac enlargement impairs the ability of the coronary circulation to allow normal increases and perfusion in response to intense dilator stimuli. In general, clinical studies have demonstrated far more profound abnormalities than studies in experimental animals. These observations provide a plausible explanation of why patients with hypertrophied ventricles often exhibit signs and symptoms of myocardial ischemia in the absence of coronary obstructive disease. The recent observation that experimentally produced left ventricular hypertrophy secondary to renal hypertension augments infarct size and the incidence of sudden lethal arrhythmias has additional implications relevant to the interaction between cardiac hypertrophy and myocardial perfusion. Although coronary reserve is impaired in many types of pathologic hypertrophy, the anatomic or biochemical basis for these observations remains elusive.
Topics: Animals; Cardiomegaly; Coronary Circulation; Coronary Disease; Humans; Hypertension; Myocardium; Vasodilation
PubMed: 2947748
DOI: No ID Found -
Schweizer Archiv Fur Tierheilkunde Jul 2010According to WHO classification hypertrophic cardiomyopathy (HCM) is a primary genetic cardiomyopathy. Echocardiographically HCM is characterized by symmetric,...
According to WHO classification hypertrophic cardiomyopathy (HCM) is a primary genetic cardiomyopathy. Echocardiographically HCM is characterized by symmetric, asymmetric or focal left ventricular hypertrophy (LVH) without recognizable underlying physical cause. However, echocardiographically HCM in cats may not be distinguishable from other causes of a thick appearing left ventricle. Hypovolemia can look like a hypertrophied ventricle but is basically only pseudohypertrophic. Well recognized and logical physical causes of LVH include systemic hypertension and outflow obstruction. LVH similar to HCM may also be found in feline hyperthyroidism. The context of the disease helps to differentiate these physical / physiological causes of LVH. Difficult to distinguish from HCM, particularly when based on a snapshot of a single echocardiographic exam, are myocarditis and <
>. Only the clinical and echocardiographic course allow a reasonably confident etiological diagnosis and the differentiation between HCM and secondary LVH. Topics: Animals; Cat Diseases; Cats; Diagnosis, Differential; Echocardiography; Genetic Diseases, Inborn; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular
PubMed: 20582898
DOI: 10.1024/0036-7281/a000075 -
Cardiology 2011It was the aim of our study to determine whether myocardial fibrosis influences physiologic or non-physiologic left ventricular (LV) hypertrophy in severe aortic...
AIM
It was the aim of our study to determine whether myocardial fibrosis influences physiologic or non-physiologic left ventricular (LV) hypertrophy in severe aortic stenosis.
METHODS
Myocardial fibrosis was evaluated using specimens taken from the ventricular septum in 79 patients submitted to aortic valve replacement because of symptomatic aortic stenosis. Patients were considered to have physiologic LV hypertrophy if end-systolic wall stress, evaluated by echocardiography, was <90 kdyn/cm(2), while those with end-systolic wall stress >90 kdyn/cm(2) were considered to have non-physiologic hypertrophy.
RESULTS
Fibrosis tissue mass index was significantly inversely related with LV fractional shortening and directly related with LV diastolic and systolic diameter and LV mass index (LVMI). Patients with non-physiologic hypertrophy (n = 24) had a higher LVMI due to larger LV diastolic and systolic diameters with thinner wall, resulting in lower relative wall thickness. These patients had a higher fibrosis tissue mass index and impaired LV systolic and diastolic functions, as suggested by lower LV fractional shortening and higher mean wedge pressure. At follow-up of 7.4 ± 2.1 months, the LVMI and New York Heart Association class remained higher in patients with non-physiologic hypertrophy.
CONCLUSIONS
Our study suggests a different quality of hypertrophies in patients with aortic stenosis, where myocardial fibrosis seems to be the critical abnormality that differentiates adaptive from maladaptive response to increased afterload.
Topics: Aged; Aged, 80 and over; Aortic Valve Stenosis; Cardiac Catheterization; Cardiomyopathies; Echocardiography, Doppler; Female; Fibrosis; Follow-Up Studies; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardium; Stress, Physiological
PubMed: 22188799
DOI: 10.1159/000334792 -
Annales de Chirurgie Plastique Et... Aug 2009The authors present a retrospective study about 20 patients operated for important breast hypertrophy and gigantomastia by the postero-inferior reduction technique. They...
The authors present a retrospective study about 20 patients operated for important breast hypertrophy and gigantomastia by the postero-inferior reduction technique. They compare the results obtained by this technique on the breast (projection, breast-feeding) and on the nipple-areola complex (sensibility, pigmentation, nipple projection), with those obtained by the Thorek technique (free nipple grafting). The authors show that this technique is reliable for such breasts hypertrophies, with good esthetics results, and avoid free nipple grafting.
Topics: Adolescent; Adult; Breast; Female; Humans; Hypertrophy; Mammaplasty; Middle Aged; Retrospective Studies; Young Adult
PubMed: 19223105
DOI: 10.1016/j.anplas.2008.10.004 -
European Journal of Pharmacology May 1987Effects of myocardial hypertrophy caused by pressure overload on sarcolemmal Na+,K+-ATPase and positive inotropic action of strophanthidin were examined in cats. Partial...
Effects of myocardial hypertrophy caused by pressure overload on sarcolemmal Na+,K+-ATPase and positive inotropic action of strophanthidin were examined in cats. Partial ligation of the main pulmonary artery for four weeks resulted in right ventricular hypertrophy with no significant changes in left ventricular muscle. Hypertrophy was associated with a reduction in the number of active Na+,K+-ATPase units. Affinity of the remaining enzyme for [3H]ouabain was unchanged. No apparent right or left shift in dose-response curve for the positive inotropic effect of strophanthidin was observed and toxic concentrations of strophanthidin were unchanged; however, the degree of the positive inotropic effect produced by high concentrations of strophanthidin was significantly smaller in hypertrophied muscle. Moreover, decreases in developed tension rather than tachyarrhythmias was the predominant form of toxicity observed in hypertrophied muscle. These results indicate that myocardial hypertrophy reduces the number of active Na+,K+-ATPase units per milligram protein, decreases maximal positive inotropic effect of strophanthidin, and alters the prevailing form of strophanthidin toxicity.
Topics: Animals; Binding Sites; Cardiac Glycosides; Cardiomegaly; Cats; Female; Male; Myocardial Contraction; Ouabain; Pressure; Sodium-Potassium-Exchanging ATPase; Strophanthidin
PubMed: 3038578
DOI: 10.1016/0014-2999(87)90184-1