Mammary hypertrophy is not associated with increased estrogen receptors

Estrogen promotes secondary female sex characteristics, including breast enlargement. Since excessive breast hypertrophy is unrelated to elevated serum estrogen levels, it has been postulated that the enlarged breast is a hypersensitive "target organ." At the cellular level, estrogen crosses the cell membrane, is bound to a cytoplasmic estrogen receptor (ER), and induces the formation of specific anabolic proteins. In breast cancer, this estrogen receptor is regarded as a measure of the sensitivity of the cell to estrogen. To determine if mammary hypertrophy is related to an increase in the number of estrogen receptors, we assayed breast tissue, not fat, from 25 consecutive breast reductions. The median age of patients was 26 years (17 to 77 years), with 752 gm per breast removed on average. Twenty-four percent of the patients were taking estrogens, primarily birth control bills. Cellular estrogen-receptor status was measured by a standardized cytosol extraction radioactive estradiol technique. Estrogen receptors were undetectable (less than 3 fmol/mg cytosol protein) in all patients. We conclude that estrogen receptors alone, and hence estrogen, are not a determinant in mammary hypertrophy. If the enlarged breast is a "target organ," it is by another mechanism.     

Mice expressing ACE only in the heart show that increased cardiac angiotensin II is not associated with cardiac hypertrophy

In the heart, angiotensin II has been suggested to regulate cardiac remodeling and promote cardiac hypertrophy. To examine this, we studied compound heterozygous mice, called angiotensin-converting enzyme (ACE) 1/8, in which one ACE allele is null, whereas the other ACE allele (the 8 allele) targets expression to the heart. In this model, cardiac ACE levels are about 15 times those of wild-type mice, and ACE expression is reduced or eliminated in other tissues. ACE 1/8 mice have 58% the cardiac ACE of a previous model, called ACE 8/8, but both ACE 1/8 and ACE 8/8 mice have ventricular angiotensin II levels about twofold those of wild-type controls. Despite equivalent levels of cardiac angiotensin II, ACE 1/8 mice do not develop the marked atrial enlargement or the conduction defects previously reported in the ACE 8/8 mice. Six-month-old ACE 1/8 mice have normal cardiac function, as determined by echocardiography and left ventricular catheterization, despite the elevated levels of angiotensin II. ACE 1/8 mice also have normal levels of connexin 43. Both wild-type and ACE 1/8 mice develop similar degrees of cardiac hypertrophy after aortic banding. These data suggest that a moderate increase of local angiotensin II production in the heart does not produce cardiac dysfunction, at least under basal conditions, and that, in response to aortic banding, cardiac hypertrophy is not augmented by a twofold increase of cardiac angiotensin II.     

Exercise-induced cardiac performance in autoimmune (Type 1) diabetes is associated with a decrease in myocardial diacylglycerol

One of the fundamental biochemical defects underlying the complications of diabetic cardiovascular system is elevation of diacylglycerol (DAG) and its effects on protein kinase C (PKC) signaling. It has been noted that exercise training attenuates poor cardiac performance in Type 1 diabetes. However, the role of PKC signaling in exercise-induced alleviation of cardiac abnormalities in diabetes is not clear. We investigated the possibility that exercise training modulates PKC-βII signaling to elicit its beneficial effects on the diabetic heart. bio-breeding diabetic resistant rats, a model reminiscent of Type 1 diabetes in humans, were randomly assigned to four groups: 1) nonexercised nondiabetic (NN); 2) nonexercised diabetic (ND); 3) exercised nondiabetic; and 4) exercised diabetic. Treadmill training was initiated upon the onset of diabetes. At the end of 8 wk, left ventricular (LV) hemodynamic assessment revealed compromised function in ND compared with the NN group. LV myocardial histology revealed increased collagen deposition in ND compared with the NN group, while electron microscopy showed a reduction in the viable mitochondrial fraction. Although the PKC-βII levels and activity were unchanged in the diabetic heart, the DAG levels were increased. With exercise training, the deterioration of LV structure and function in diabetes was attenuated. Notably, improved cardiac performance in training was associated with a decrease in myocardial DAG levels in diabetes. Exercise-induced benefits on cardiac performance in diabetes may be mediated by prevention of an increase in myocardial DAG levels.     

Exercise-induced cardiac hypertrophy: a correlation of blood flow and microvasculature

The effects of exercise conditioning on the myocardium were studied in seven instrumented pigs strenuously exercised for 12 wk by treadmill running. Data were compared with eight instrumented untrained pigs. O2 consumption measured during maximum exercise effort was significantly elevated in the trained pigs (71.7 +/- 4.0 vs. 56.3 +/- 3.0 ml X ml-1 X kg-1). Absolute right and left ventricular mass increased by 20 and 13%, respectively, in response to exercise. Myocyte cross-sectional area increased by 21% in the trained hearts compared with the untrained hearts. Transmural left ventricular myocardial blood flow (ml X min-1 X g-1) was not significantly different at rest, during maximum exercise, or during exercise with adenosine infusion. However, training caused an elevation of the regional epicardial blood flow noted during exercise and exercise with adenosine. In the trained pigs mean aortic pressure during maximum exercise with adenosine infusion was not significantly different compared with untrained pigs. Coronary resistance during exercise with adenosine infusion was the same in both animal groups. In the trained group capillary numerical (no./mm2) and length (mm/mm3) densities were reduced, whereas arteriolar numerical and length densities were significantly increased compared with the untrained group. Measurements of capillary luminal surface density (mm2/mm3) in the trained group were unchanged compared with the untrained group. These results suggest that strenuous exercise does not stimulate the production of new capillaries, but this is modified by the ability of existing capillaries to increase their luminal surface area to parallel increases in myocyte growth. The arteriolar data suggest that exercise promotes the formation of new arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rosiglitazone is not associated with an increased risk of bladder cancer

BackgroundWhether rosiglitazone may increase bladder cancer risk has not been extensively investigated.MethodsThe reimbursement databases of all Taiwanese diabetic patients under oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2006 and a total of 885,236 patients with type 2 diabetes were followed up for bladder cancer incidence till end of 2009. Incidences for ever-users, never-users and subgroups of rosiglitazone exposure (using tertile cutoffs of time since starting rosiglitazone, duration of therapy and cumulative dose) were calculated and hazard ratios estimated by Cox regression.ResultsThere were 102,926 ever-users and 782,310 never-users, respective numbers of incident bladder cancer 356 (0.35%) and 2753 (0.35%), and respective incidence 98.3 and 101.6 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) did not show significant association in unadjusted model [0.969 (0.867, 1.082)] and models adjusted for age and sex [0.983 (0.880, 1.098)] or all covariates [0.980 (0.870, 1.104)]. Neither the P values for the hazard ratios for the different categories of the dose–responsive parameters, nor their P-trends were significant.ConclusionsRosiglitazone does not increase the risk of bladder cancer.     

Mitral prolapsing volume is associated with increased cardiac dimensions in patients with mitral annular disjunction

Netherlands Heart Journal - In patients with mitral annular disjunction (MAD), it can be difficult to assess the severity of mitral regurgitation (MR), as they present with a prolapsing...     

PKC-beta is not necessary for cardiac hypertrophy

Studies in human and rodent models have shown that activation of protein kinase C-beta (PKC-beta) is associated with the development of pathological hypertrophy, suggesting that ablation of the PKC-beta pathway might prevent or reverse cardiac hypertrophy. To explore this, we studied mice with targeted disruption of the PKC-beta gene (knockout, KO). There were no detectable differences in expression or distribution of other PKC isoforms between the KO and control hearts as determined by Western blot analysis. Baseline hemodynamics were measured using a closed-chest preparation and there were no differences in heart rate and arterial or left ventricular pressure. Mice were subjected to two independent hypertrophic stimuli: phenylephrine (Phe) at 20 mg x kg(-1) x day(-1) sq infusion for 3 days, and aortic banding (AoB) for 7 days. KO animals demonstrated an increase in heart weight-to-body weight ratio (Phe, 4.3 +/- 0.6 to 6.1 +/- 0.4; AoB, 4.0 +/- 0.1 to 5.8 +/- 0.7) as well as ventricular upregulation of atrial natriuretic factor mRNA analogous to those seen in control animals. These results demonstrate that PKC-beta expression is not necessary for the development of cardiac hypertrophy nor does its absence attenuate the hypertrophic response.     

Late-gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis

BACKGROUND : Previous work in our laboratory showed reduced myocardium and dilated ventricular chambers in gestation day (GD) 17 hearts that were collected from hyperglycemic CD1 mouse dams. Pre-breeding maternal immune stimulation, using Freund's complete adjuvant (FCA), diminished the severity of these fetal heart lesions. The following experiments were performed to detect possible changes in fetal heart apoptotic cell death, under hyperglycemic conditions and with or without maternal immune stimulation. METHODS : Female CD1 mice were injected with 200 mg/kg of streptozocin (STZ) to induce insulin-dependent diabetes mellitus. Half of these mice received prior FCA injection. Fetal hearts were collected on GD 17 and myocardial apoptotic cells were quantified using flow cytometry. A panel of apoptosis regulatory genes (Bcl2, p53, Casp3, Casp9, PkCe) was then examined in the fetal myocardium using RT-PCR. RESULTS : Early apoptotic cells and late apoptotic/necrotic cells were significantly increased in fetal hearts from STZ or STZ+FCA dams. Pre-treatment with FCA reduced late apoptotic/necrotic cells to control level, suggesting some cell death protection was rendered by FCA. Paradoxically in the face of such increased cell death, the expression of pro-apoptotic genes Casp3 and Casp9 was decreased by diabetes, while the anti-apoptotic gene Bcl2 was increased. CONCLUSIONS : Maternal hyperglycemia causes dys-regulated apoptosis of fetal myocardial cells. Such effect may be prevented by maternal immune stimulation. Birth Defects Res (Part B) 86:409–415, 2009. © 2009 Wiley-Liss, Inc.     

Reduced cardiac stiffness following exercise is associated with preserved myocardial collagen characteristics in the rat

We determined whether the increment in cardiac end-diastolic compliance (a reduced diastolic stiffness constant) following endurance training is related to alterations in myocardial collagen characteristics. Sixteen weeks of habitual exercise (Ex) in rats, which produced left ventricular (LV) hypertrophy (LVH) [LV weight in g: Ex=1.01 (0.04), sedentary control = 0.89 (0.04); P<0.05], resulted in a reduced LV end-diastolic (LVED) chamber stiffness [slope of the linearised LVED pressure versus LVED internal diameter relation in kPa · mm⁻¹: Ex=0.67 (0.03), control=0.80 (0.03); P<0.05]. The increased LVED chamber distensibility was associated with an attenuated myocardial stiffness [slope of the linearised LVED stress versus strain relation in g · cm⁻²; Ex=15 (3), control=25 (2); P<0.05]. Although LV total collagen content (mg) was increased in the exercised rats [Ex=5.0 (0.3), control=4.1 (0.2); P<0.05], this was a reflection of the presence of LVH, as the myocardial collagen concentration (μg · mg⁻¹ LV wet weight) was unaltered [Ex=4.9 (0.2), control=4.6 (0.2)]. Furthermore, habitual exercise did not influence the percentage of myocardial collagen extracted following cyanogen bromide digestion (an index of collagen cross-linking), [i.e. Ex=38 (3), control=38 (3)], nor the proportion of myocardial collagen phenotypes I and III [I/III; Ex=3.04 (0.20), control=2.85 (0.22)]. In conclusion, exercise-induced increments in end-diastolic myocardial distensibility are unlikely to be a consequence of alterations in the properties of myocardial collagen. Accepted: 17 December 1997     

Constraints on cardiac hypertrophy imposed by myocardial viscosity.

Laplace's law constrains how thin the ventricular wall may be without experiencing excessive stress. The present study investigated constraints, imposed by myocardial viscosity (resistance to internal rearrangement), on how thick the wall may be. The ventricle was modeled as a contracting, spherical shell. The analysis demonstrated that viscosity generates stress and energy dissipation with inverse fourth- and eighth-power dependence, respectively, on distance from the cavity center. This result derives from the combination of squared dependence of viscous forces on shearing velocity gradients and the greater shear rearrangement required for inner layers of a contracting sphere. These predictions are based solely on geometry and fundamentals of viscosity and are independent of material properties, cytoskeletal structure, and internal structural forces. Calculated values of energy and force required to overcome viscosity were clearly large enough to affect the extent of thickening of the left ventricle. It is concluded that load-independent viscous resistance to contraction is an important factor in cardiac mechanics, especially of the thickened ventricles of concentric hypertrophy.     

Thrombocytopenia in an animal model of malaria is associated with an increased caspase-mediated death of thrombocytes

Infection of mice with Plasmodium Berghei Anka (PbA) leads to a thrombocytopenia, due to a reduced platelet life span, eventually associated with a syndrome of severe or cerebral malaria (CM). Thrombocytopenia was associated with an increase in the number of microparticles (mcp) in plasma. More than >60% of these mcp were of platelet origin, as seen by staining with an anti-platelet antibody. The thrombocytopenia and the amount of mcp were decreased in mice treated with anti CD40L mAb, suggesting that CD40L is the main effector of the thrombocytopenia. Caspase-1, -3, -6, -8, -9 were activated in platelets from infected mice, as seen by the binding of labeled probes or the amount of pro-caspase-3. Treatment of infected mice with the caspases inhibitor ZVAD-fmk decreased the number of mcp and the thrombocytopenia, shoving that platelet caspases are responsible for platelet fragmentation. In addition, the caspase inhibitor also caused a decrease in the mortality associated with CM, indicating a critical role of caspases in the expression of CM.     

Myocardial injury after ischemia-reperfusion in mice deficient in Akt2 is associated with increased cardiac macrophage density

Akt2 protein kinase has been shown to promote cell migration and actin polymerization in several cell types, including macrophages. Because migrating macrophages constitute an important inflammatory response after myocardial ischemia, we determined cardiac macrophage expression after ischemia-reperfusion (I/R) injury and cryo-injury in mice lacking Akt2 (Akt2-KO). At 7 days post-I/R, Akt2-KO cardiac tissues showed an increase in immunohistochemical staining for macrophage markers (Galectin 3 and F4/80) compared with wild-type (WT) mice, indicating macrophage density was increased in the injured Akt2-KO myocardium. This change was time dependent because macrophage density was similar between WT and Akt2-KO myocardium at 3 days post-I/R, but by 7 and 14 days post-I/R, macrophage density was significantly increased in Akt2-KO myocardium. Concomitantly, infarct size was larger and cardiac function was reduced in Akt2-KO mice subjected to I/R. However, when cryo-infarction produced similar infarct sizes in the anterior wall in both WT and Akt2-KO mice, macrophage density remained higher in Akt2-KO mouse myocardium, suggesting Akt2 regulates myocardial macrophage density independent of infarct size. Consistently, bone marrow from Akt2-KO mice enhanced myocardial macrophage density in both C57/B6 WT and Akt2-KO recipient mice. Finally, reciprocal ex-vivo coculturing of macrophages and cardiac myocytes showed that activated Akt2-KO peritoneal macrophages had reduced mobility and adhesion when compared with WT littermate controls. Thus, although Akt-2 KO mice did not affect the initial inflammation response after injury and Akt2 deficiency has been shown to impair cell migration or motility in macrophages, our data suggested a novel mechanism in which increasing retention of Akt2-KO macrophages resulted in increasing cardiac Akt2-KO macrophage density in the myocardial space.     

Obesity in older adults is associated with an increased prevalence and incidence of pain

Cross-sectional studies suggest an association between BMI and pain. This prospective study investigated the associations of measured BMI and waist circumference with prevalent and incident pain in older adults. The study included participants of the Longitudinal Aging Study Amsterdam, aged 55-85 years at baseline (1992-1993). Pain was assessed using a subscale of the Nottingham Health Profile at baseline (N = 2,000), after 3 years (N = 1,478) and 6 years (N = 1,271) of follow-up. The overall prevalence of pain was 32.7% at baseline and increased significantly with higher quartiles of BMI or waist circumference. After adjustment for age, education, depression, smoking, physical activity, and chronic diseases, multiple logistic regression analyses showed odds ratios (ORs (95% confidence interval)) for prevalent pain of 2.16 (1.32-3.54) in men and 1.93 (1.26-2.95) in women comparing the highest with the lowest quartile of BMI. Of the participants without pain at baseline, those in the highest quartile of BMI had a twofold increased odds for incident pain after 3 years of follow-up. After 6 years of follow-up, ORs for incident pain were 2.34 (1.17-4.72) in men and 2.78 (1.36-5.70) in women. Additional adjustment for weight change did not change these associations. Similar results were found for the associations between waist circumference and pain. Exploring the reversed causal relation, analyses showed no significant associations between prevalent pain and weight gain. In conclusion, the prevalence of pain is higher among obese older men and women compared to their normal-weight peers. Furthermore, obese older adults are at increased odds to develop pain.     

Polydatin prevents angiotensin II-induced cardiac hypertrophy and myocardial superoxide generation

Our studies and others recently demonstrate that polydatin, a resveratrol glucoside, has antioxidative and cardioprotective effects. This study aims to investigate the direct effects of polydatin on Ang II-induced cardiac hypertrophy to explore the potential role of polydatin in cardioprotection. Our results showed that in primary cultured cardiomyocytes, polydatin blocked Ang II-induced cardiac hypertrophy in a dose-dependent manner, which were associated with reduction in the cell surface area and [³H]leucine incorporation, as well as attenuation of the mRNA expressions of atrial natriuretic factor and β-myosin heavy chain. Furthermore, polydatin prevented rat cardiac hypertrophy induced by Ang II infusion, as assessed by heart weight-to-body weight ratio, cross-sectional area of cardiomyocyte, and gene expression of hypertrophic markers. Further investigation demonstrated that polydatin attenuated the Ang II-induced increase in the reactive oxygen species levels and NADPH oxidase activity in vivo and in vitro. Polydatin also blocked the Ang II-stimulated increases of Nox4 and Nox2 expression in cultured cardiomyocytes and the hearts of Ang II-infused rats. Our results indicate that polydatin has the potential to protect against Ang II-mediated cardiac hypertrophy through suppression of NADPH oxidase activity and superoxide production. These observations may shed new light on the understanding of the cardioprotective effect of polydatin.