Pathogenesis Of Myocardial Hypertrophy Research Articles

Vitamin D Attenuates Cardiac Hypertrophy in Rats through mRNA Regulation of Interleukin-6 and Its Receptor

Abstract Context: Interleukin-6 (IL-6), a pro-inflammatory cytokine, plays an important role in the pathogenesis of myocardial hypertrophy. By integrating its membrane receptor complex (gp80), IL-6 activates the signal guidance components (gp130) and activates the hypertrophic signaling pathways. There is some evidence that 1,25 dihydroxyvitamin D exerts antihypertrophic effects, but the cellular and molecular mechanisms are not fully understood. The aim of this study was to evaluate the effect of calcitriol on the level of IL-6 and its receptor components in hypertrophied rat heart. Subjects and Methods: Male rats were divided into control, hypertrophy, Vitamin D + hypertrophy, and propylene glycol + hypertrophy groups. The groups receiving Vitamin D and propylene glycol were treated 2 weeks before induction of hypertrophy and 2 weeks after hypertrophy. Myocardial hypertrophy was induced by abdominal aortic stenosis. Mean arterial blood pressure was measured by cannulation of the left carotid artery, and expression of genes was determined by reverse transcription-polymerase chain reaction. Results: Blood pressure and heart-to-body weight ratio increased in hypertrophic groups compared to the control group (P < 0.01), but Vitamin D administration decreased these parameters (P < 0.05). Abdominal aortic stenosis increased IL-6 expression levels (P < 0.001) and Vitamin-D decreased IL-6 mRNA levels (P < 0.01). The expression of gp80 in the hypertrophic group increased compared to the control group (P < 0.05), but Vitamin D did not affect the expression of receptor subunits genes. Conclusions: The data from this study suggest a possible mechanism for the antihypertrophic effects of Vitamin D through the regulation of inflammatory responses during hypertrophy. Thus, Vitamin D can reduce IL-6 expression levels, thereby reducing hypertrophy.

Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene.

Background Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6, respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

Significance of aldosterone synthase gene (CYP11B2) polymorphism as a component of the renin-angiotensin-aldosterone system in the pathogenesis of myocardial hypertrophy in hypertension: literature review and own experience

Aldosterone synthase gene is one of the candidate genes responsible for the effects of aldosterone. In particular, there are some evidences concerning the influence of this gene on the myocardial remodeling in hypertension. The analysis and summary of the results of published researches devoted to the study of aldosterone synthase gene (CYP11B2) polymorphism and its importance in the processes of hypertensive myocardial remodeling are presented in the article. Pub Med and EMBASE databases were used. The results of the study of CYP11B2 polymorphism within the framework of the research work at the Department of Internal Medicine of Medical Faculty №2 are presented in the article. The aim of the study is to study the importance of polymorphism of aldosterone synthase gene in the pathogenesis and clinic of hypertension. It has been shown that among both, hypertensive and males, residents of Podillia region of Ukraine, the overwhelming majority were carriers of TC polymorphism of CYP11B2 gene. These data are in the agreement with the previous studies in the European population.

MiRNA-mRNA crosstalk in myocardial ischemia induced by calcified aortic valve stenosis.

Aortic valve stenosis is the most common cause of morbidity and mortality in valvular heart disease in aged people. Both microRNA (miRNA) and mRNA are potential targets for the diagnosis and therapeutic intervention of myocardial ischemia induced by calcified aortic valve stenosis (CAVS), with unclear mechanisms. Here, 3 gene expression profiles of 47 male participants were applied to generate shared differentially expressed genes (DEGs) with significant major biological functions. Moreover, 20 hub genes were generated by a Weighted Genes Co-Expression Network Analysis (WGCNA) and were cross-linked to miRNA based on miRanda/miRwalk2 databases. Integrated miRNA/mRNA analysis identified several novel miRNAs and targeted genes as diagnostic/prognostic biomarkers or therapeutic targets in CAVS patients. In addition, the clinical data suggested that myocardial hypertrophy and myocardial ischemia in CAVS patients are likely associated with hub genes and the upstream regulatory miRNAs. Together, our data provide evidence that miRNAs and their targeted genes play an important role in the pathogenesis of myocardial hypertrophy and ischemia in patients with CAVS.

Is FGF-23 an early indicator of atherosclerosis and cardiac dysfunction in patients with gestational diabetes?

Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone and plays a role in the pathogenesis of myocardial hypertrophy. The aim of this study was to evaluate the association of FGF-23 levels with echocardiographic parameters and insulin resistance (IR) in patients with gestational diabetes. Fifty-four pregnant patients with gestational diabetes mellitus (GDM) (age, 31.12 ± 5.72 years) and 33 healthy pregnant women (age, 29.51 ± 4.92 years) were involved in the study. Fasting insulin, fasting plasma glucose (FPG), lipid profile, oral glucose tolerance test (OGTT), FGF23, echocardiographic parameters, and carotid artery intima-media thickness (CIMT) were evaluated in the two groups. The two groups were not significantly different in age, sex, body mass index, lipid profile, or blood pressure. Insulin, homeostatic model assessment-insulin resistance (HOMA-IR), FGF-23 levels, CIMT, left ventricular (LV) mass, LV mass index and myocardial performance index (MPI) were significantly higher in the GDM group. HOMA-IR was positively correlated with FGF-23, and insulin was positively correlated with FGF-23. Additionally, FGF-23 was positively correlated with CIMT, LV mass index, and MPI. Our findings suggest that monitoring serum FGF-23 may be useful as a non-invasive indicator of subclinical atherosclerosis in patients with GDM.

Research progress on the role of regulators of G-protein signaling in the pathogenesis of myocardial hypertrophy

Research progress on the role of regulators of G-protein signaling in the pathogenesis of myocardial hypertrophy

Protective effect of hydrogen sulphide against myocardial hypertrophy in mice.

Cardiac hypertrophy is a critical component of phenotype in the failing heart. Recently, increasing evidence has demonstrated that oxidative stress plays an important role in the pathogenesis of myocardial hypertrophy. In the present study, we generated a mouse model of transverse aortic constriction (TAC) to investigate whether hydrogen sulfide (H2S) has protective effects against cardiac hypertrophy. Left ventricular structure was analyzed by two-dimensional echocardiography. Oxidative stress was evaluated by measuring malondialdehyde, superoxide dismutase, glutathione peroxidase and reactive oxygen specie in the myocardium. Angiotensin II (Ang-II) was used to induce cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes pretreated with H2S donor sodium hydrosulfide prior to Ang-II exposure were used to determine the involvement of Nrf2 and PI3K/Akt pathway in the antioxidant effects of H2S. Our findings showed that H2S could protect against cardiac hypertrophy by attenuating oxidative stress. The antioxidant roles of H2S in myocardial hypertrophy probably depend on the activation of PI3K/Akt signaling, which consequently increases Nrf2 activity and HO-1 and GCLM expression. In summary, H2S may exert antioxidant effect on cardiac hypertrophy via PI3K/Akt-dependent activation of Nrf2 pathway.

Downregulated endogenous sulfur dioxide/aspartate aminotransferase pathway is involved in angiotensin II-stimulated cardiomyocyte autophagy and myocardial hypertrophy in mice

BackgroundThe study was designed to investigate if endogenous sulfur dioxide (SO2) was involved in cardiomyocyte autophagy and myocardial hypertrophy stimulated by angiotensin II (Ang II). MethodsThirty-two C57 mice were randomly divided into control, SO2, Ang II and Ang II+SO2 groups. Human myocardial cell line H9c2 was divided into four groups including control, SO2, Ang II and Ang II+SO2 groups. Blood pressure and myocardial hypertrophy of the mice were measured two weeks after Ang II administration. LC3 II/I ratio, and Beclin1, Atg4B and p62 expressions were determined both in vivo and in vitro. Autophagosome was observed in H9c2 cells with confocal microscope. Endogenous SO2 generation and aspartate aminotransferase (AAT) expression were measured. ResultsIn animal studies, hypertension and myocardial hypertrophy developed two weeks after Ang II administration. LC3 II/I ratio and Beclin1 and Atg4B expressions were markedly elevated (P all <0.05), but p62 expression was lowered (P<0.05) both in vivo and in vitro. Compared with control group, endogenous SO2 levels, AAT activity and AAT2 expression were obviously down-regulated (P all <0.05). However, SO2 donor significantly reduced Ang II-induced myocardial hypertrophy in mice. LC3 II/I ratio and Beclin1 and Atg4B expressions were down-regulated (P all <0.05) but p62 expression was significantly increased (P<0.05) in the presence of SO2 both in vivo and in vitro. ConclusionDown-regulated endogenous SO2/AAT2 pathway might be involved in the pathogenesis of myocardial hypertrophy. SO2 prevented Ang II -induced myocardial hypertrophy accompanied by down-regulating cardiomyocyte autophagy.

Fibroblast growth factor is associated to left ventricular mass index, anemia and low values of transferrin saturation

BackgroundFibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. Left ventricular hypertrophy (LVH) is a potent risk factor for mortality in CKD, and FGFs have been implicated in the pathogenesis of myocardial hypertrophy. In addition, the effect of anemia on CV disease and LVH is well known in CKD. A relation between iron and FGF-23 metabolism is mentioned in a few studies. The aim of this study was to test the association of FGF-23 levels with echocardiographic (ECHO) and iron parameters in peritoneal dialysis patients (PD). MethodsIn this cross-sectional study, 61 subjects with PD (29 women and 32 men, mean age: 46.9±13.3 years, mean PD vintage: 69.5±39 months) underwent echocardiograms to assess left ventricular mass index (LVMI). Medical treatments and average values of the basic laboratory results of the last 6 months for all patients were recorded. Serum FGF-23 concentrations were measured using intact FGF-23 (iFGF-23) human enzyme-linked immunosorbent assay (ELİSA) kit. According to the median levels of serum FGF-23 the patients were grouped into two (FGF-23 high and low groups). ResultsSignificant positive correlation was recorded between serum FGF-23 levels and LVMI (P=0.023). There was also significant difference in terms of hemoglobin (12.1±2 versus 11.0±2, P=0.017), transferrin saturation (TSAT) (24.9±16.8 versus 19.5±10.8, P=0.042) between low and high FGF-23 group. Also in linear regression analysis the negative relation between FGF-23 and hemoglobin is persisted (r=0.199, P=0.045). ConclusionsFGF-23 is associated with LVMI, anemia and low TSAT in patients with PD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy and anemia in patients with end-stage renal disease (ESRD) requires further study.

Fibroblast growth factor is associated to left ventricular mass index, anemia and low values of transferrin saturation

BackgroundFibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. Left ventricular hypertrophy (LVH) is a potent risk factor for mortality in CKD, and FGFs have been implicated in the pathogenesis of myocardial hypertrophy. In addition, the effect of anemia on CV disease and LVH is well known in CKD. A relation between iron and FGF-23 metabolism is mentioned in a few studies. The aim of this study was to test the association of FGF-23 levels with echocardiographic (ECHO) and iron parameters in peritoneal dialysis patients (PD). MethodsIn this cross-sectional study, 61 subjects with PD (29 women and 32 men, mean age: 46.9±13.3 years, mean PD vintage: 69.5±39 months) underwent echocardiograms to assess left ventricular mass index (LVMI). Medical treatments and average values of the basic laboratory results of the last 6 months for all patients were recorded. Serum FGF-23 concentrations were measured using intact FGF-23 (iFGF-23) human enzyme-linked immunosorbent assay (ELİSA) kit. According to the median levels of serum FGF-23 the patients were grouped into two (FGF-23 high and low groups). ResultsSignificant positive correlation was recorded between serum FGF-23 levels and LVMI (P=0.023). There was also significant difference in terms of hemoglobin (12.1±2 versus 11.0±2, P=0.017), transferrin saturation (TSAT) (24.9±16.8 versus 19.5±10.8, P=0.042) between low and high FGF-23 group. Also in linear regression analysis the negative relation between FGF-23 and hemoglobin is persisted (r=0.199, P=0.045). ConclusionsFGF-23 is associated with LVMI, anemia and low TSAT in patients with PD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy and anemia in patients with end-stage renal disease (ESRD) requires further study.

Circulating mesenchymal stem cells in patients with hypertrophic cardiomyopathy.

This study examines the mobilization of mesenchymal stem cells (MSCs) in patients with hypertrophic cardiomyopathy (HCM) compared to healthy individuals. The pathogenesis of myocardial hypertrophy in HCM is not fully understood. MSCs are involved in the process of neovascularization, fibrosis, and ventricular wall remodeling. We included 40 patients with HCM and 23 healthy individuals. Using flow cytometry, we measured MSCs in peripheral blood, as a population of CD45-/CD34-/CD90+ cells and also as a population of CD45-/CD34-/CD105+ cells. The resulting MSC counts were expressed as percentages of the total cells. Patients with HCM were found to have a greater percentage of circulating CD45-/CD34-CD34-/CD90+ cells compared to controls (0.0041±0.005% vs. 0.0007±0.001%, respectively, P<.001). No significant difference in circulating CD45-/CD34-/CD105+ cells in the peripheral blood was found between HCM patients and controls (0.016±0.018% vs. 0.012±0.014%, respectively, P=.4). Notably, circulating CD45-/CD34-/CD90+ cells were positively correlated with left ventricular mass index (r=0.54, P<.001). Patients with HCM reveal an increased mobilization of MSCs compared to healthy individuals. Although further research is needed to reveal the clinical significance of our findings, our data open a new dimension in the pathophysiology of the disease and may indicate new future therapeutic possibilities.

Abstract 18105: Genetic Deletion of IL-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Failure

Increasing evidence indicates a role of proinflammatory cytokines in the pathogenesis of myocardial hypertrophy and failure. Chronic interleukin-6 (IL-6) stimulation leads to LV hypertrophy and dysfunction, and deletion of IL-6 reduces LV hypertrophy after angiotensin II infusion. In this study, we tested the hypothesis that genetic deletion of IL-6 would ameliorate pressure overload-induced myocardial hypertrophy and failure. We performed transverse aortic constriction (TAC) in IL-6 knockout (IL6 KO) mice and wild-type (WT) C57BL/6J mice (control) to induce pressure overload. Cardiac structure and function were assessed by serial echocardiography prior to and until 42 days after TAC. Pressure overload induced progressive LV hypertrophy, remodeling, and dysfunction in WT control mice compared with baseline (BSL) (Figure). At 6 wks after TAC, these adverse effects of pressure overload were significantly attenuated in IL6 KO mice, as evidenced by smaller LV mass and greater LV EF compared with controls (Figure). We conclude that genetic deletion of IL-6 attenuates LV remodeling and dysfunction induced by pressure overload. These data suggest a possible therapeutic potential of IL-6 inhibition to ameliorate LV hypertrophy and dysfunction in patients with systemic hypertension.

Review: β‐Blockade in Chronic Dialysis Patients

AbstractApproximately 50% of the mortality in chronic dialysis patients is due to cardiovascular diseases (CVD). Cardiomyopathy, coronary artery disease, and arrhythmia are all common conditions and predispose to sudden death, which accounts for 60% of all cardiac deaths in this population. Despite advances in dialysis therapy, the mortality from CVD remains substantially unchanged, partly due to the lack of evidence‐based strategies for improving the outcome of cardiac diseases in this population. Activation of the sympathetic adrenergic system is well documented in chronic dialysis patients and is likely involved in the pathogenesis of myocardial hypertrophy, coronary artery disease, heart failure, and arrhythmia. Given the proven benefit of β‐blockers in patients with normal kidney function with similar cardiac comorbidities, β‐blockers would seem to be attractive agents to reduce cardiovascular morbidity and mortality in the patient population with advanced chronic kidney disease. However, the value of β‐blockade in patients on chronic dialysis remains unclear. This uncertainty surrounding the efficacy is compounded by the risk of side effects to these patients, such as hypotension, bradycardia, and hyperkalemia. In addition, numerous studies have suggested suboptimal usage of β‐blockers in the dialysis population; this is seen even in high risk patients, such as those with established coronary artery disease. In this review, we will focus on sympathetic nervous system activation in kidney disease and highlight the benefit and risks of β‐blockers usage in the chronic dialysis patient population.

PTEN/PI3K pathways are involved in the signal transduction of myocardial remodeling in patients with congestive heart failure

To investigate the roles of PTEN (phosphatase and tensin homologue deleted on chromosome ten)/PI3K (phosphatidylinositol 3 kinase) signal transduction pathways in myocardium remodeling in patients with congestive heart failure (CHF). A small amount of papillary muscle tissue was collected during mitral valve displacement from 39 patients of mitral valve disease with CHF, 12 cases with grade II, 15 cases with grade III, and 12 cases with grade IV cardiac function. 30 cases of healthy persons and 8 cases of heart donors who died of accident were included as controls. Pathological examination was conducted. Immunoprecitipation was used to assay the protein expression and phosphorylation of PTEN, PI3K and Akt (protein kinase B), and protein expression of alpha-skeletal-actin in myocardial tissues. Typical myocardial remodeling was shown in the myocardial tissues from the valvular heart disease patients with CHF. Hypertrophy was dominant in the myocardial tissues at early stagy of CHF, the myocardial tissues in the end stage of CHF was characterized by disordered alignment of myocytes, discontinuity and dissolving of cardiac fiber, destroyed subcellular organs, and hyperplasia of interstitial tissue. The protein expression of PTEN [absorbance value (A) ratio of PTEN and beta-actin] in control group was 3.29 +/- 0.11, grade II cardiac function was 2.56 +/- 0.19, grade III was 1.52 +/- 0.35, grade IV was 0.91 +/- 0.10, PTEN protein expressions in CHF groups were lower than that of control group and negatively correlated to the levels of cardiac function (P < 0.05 or 0.01). On the contrary, The phosphorylation of PI3K (PI3K/beta-actin) in control group was 0.21 +/- 0.04, grade II cardiac function was 0.52 +/- 0.09, grade III was 1.12 +/- 0.29, grade IV was 1.62 +/- 0.54; The phosphorylation of Akt (Akt/beta-actin) in control group was 0.75 +/- 0.13, grade II cardiac function was 1.21 +/- 0.34, grade III was 2.45 +/- 0.71, grade IV was 3.55 +/- 0.80; The protein expression of alpha-skeletal-actin (alpha-skeletal-actin/beta-actin) in control group was 0.20 +/- 0.03, grade II cardiac function was 0.41 +/- 0.04, grade III was 0.82 +/- 0.09, grade IV was 1.56 +/- 0.11, their expressions in CHF groups were higher than that of control group and positively correlated to the levels of cardiac function (P < 0.05 or 0.01). Both the PTEN and PI3K signal pathways are involved in the pathogenesis of myocardial remodeling in CHF patients with valvular heart disease, which play an important role in the pathogenesis of myocardial hypertrophy. PTEN may play a negative regulation role in the process of myocardial remodeling.

Physiological Growth Synergizes With Pathological Genes in Experimental Cardiomyopathy

Hundreds of signaling molecules have been assigned critical roles in the pathogenesis of myocardial hypertrophy and heart failure based on cardiac phenotypes from alpha-myosin heavy chain-directed overexpression mice. Because permanent ventricular transgene expression in this system begins during a period of rapid physiological neonatal growth, resulting phenotypes are the combined consequences of transgene effects and normal trophic influences. We used temporally-defined forced gene expression to investigate synergy between postnatal physiological cardiac growth and two functionally divergent cardiomyopathic genes. Phenotype development was compared various times after neonatal (age 2 to 3 days) and adult (age 8 weeks) expression. Proapoptotic Nix caused ventricular dilation and severe contractile depression in neonates, but not adults. Myocardial apoptosis was minimal in adults, but was widespread in neonates, until it spontaneously resolved in adulthood. Unlike normal postnatal cardiac growth, concurrent left ventricular pressure overload hypertrophy did not synergize with Nix expression to cause cardiomyopathy or myocardial apoptosis. Prohypertrophic Galphaq likewise caused eccentric hypertrophy, systolic dysfunction, and pathological gene expression in neonates, but not adults. Thus, normal postnatal cardiac growth can be an essential cofactor in development of genetic cardiomyopathies, and may confound the interpretation of conventional alpha-MHC transgenic phenotypes.

Cardiac Calcineurin during Transition from Hypertrophy to Heart Failure in Rats

We studied an alteration of calcineurin expression in the heart and its modification by cyclosporin A and an ACE inhibitor, temocapril, using Dahl salt-sensitive (DS) rats with hypertensive left ventricular hypertrophy (LVH) and congestive heart failure (CHF). Calcineurin protein expression in the LV myocardium was increased in the LVH stage, but then decreased during CHF transition. Chronic cyclosporin A treatment (10 mg/kg/day), which inhibits calcineurin activity, could not block the increases of LV weight and dimensions and did not improve the LV systolic function during the CHF transition. In contrast, chronic temocapril treatment (20 mg/kg/day) restored the downregulation of calcineurin expression, but progression of the hypertrophic process was inhibited. Therefore, cardiac calcineurin is increased in the hypertensive LVH and may be involved in the development of the adaptive hypertrophic process. However, calcineurin expression is downregulated during CHF transition and may no longer play a major role in the pathogenesis of myocardial hypertrophy in the failing hearts.

The role of Jak/STAT signaling in heart tissue renin-angiotensin system.

The involvement of the Renin Angiotensin System (RAS) and the role of its primary effector, angiotensin II (Ang II), in etiology of myocardial hypertrophy and ischemia is well documented. In several animal models, the RAS is activated in cardiac cell types that express the receptor AT1, and/or AT2, through which the Ang II mediated effects are promoted. In this article, we briefly review recent experimental evidence on the critical role of a prominent signaling pathway, the Jak/STAT pathway in activation and maintenance of the local RAS in cardiac hypertrophy and ischemia. Recent studies in our laboratory document that the promoter of the prohormone angiotensinogen (Ang) gene serves as the target site for STAT proteins, thereby linking the Jak/STAT pathway to activation of heart tissue autocrine Ang II loop. STAT5A and STAT6, are selectively activated when the heart is subjected to ischemic injury, whereas activation of STAT3 and STAT5A is involved in myocardial hypertrophy. Blockage of RAS activation by treatment with specific inhibitor promotes a remarkable recovery in functional hemodynamics of the myocardium. Thus, activation of selective sets of STAT proteins constitutes the primary signaling event in the pathogenesis of myocardial hypertrophy and ischemia.

The role of guanine nucleotide binding proteins in hamsters with myocardial hypertrophy.

To clarify the role of the guanine nucleotide binding proteins (G-proteins) in the pathogenesis of myocardial hypertrophy, we investigated the alterations in myocardial G proteins in 20-week-old F1b hamsters with pressure overload induced for 3 days (3-day AS), 7 days (7-day AS) and 14 days (14-day AS) by the stenosis of the abdominal aorta, and in 4- and 20 week-old BIO 14.6 Syrian hamsters (4-wk and 20-wk BIO) with genetic myocardial hypertrophy. The hearts of 7-day AS, 14-day AS and 20-wk BIO with left ventricular hypertrophy exhibited a decrease in the mRNA levels detected by Northern blot analysis and protein levels of G protein detected by Western blot analysis as compared with sham-operated and age-matched F1b hearts. The function of Gs or Gi showed a concomitant reduction in both models of myocardial hypertrophy. The hearts of 3-day AS and 4-wk BIO without myocardial hypertrophy showed no changes in G proteins as compared with sham-operated and age-matched F1b hearts. These results suggest that a decrease in G proteins is not involved in the pathogenesis of myocardial hypertrophy, but that myocardial hypertrophy reduced the G proteins.

Sympathetic modulation of the cardiac myocyte phenotype: studies with a cell-culture model of myocardial hypertrophy.

Myocardial hypertrophy is the common endpoint of many cardiovascular stimuli such as hypertension, myocardial infarction, valvular disease, and congestive failure. Catecholamines have long been implicated in the pathogenesis of myocardial hypertrophy, however, it is very difficult to sort out catecholamine mechanisms in vivo. We have developed a cell-culture model which excludes hemodynamic effects and allows the assignment of receptor specificity to catecholamine effects. Utilizing this system, we have shown that stimulation of the alpha 1 adrenergic receptor leads to the development of myocardial hypertrophy and results in the selective up-regulation of the fetal/neonatal mRNAs encoding skeletal alpha-actin and beta-MHC, a pattern similar to that seen with hypertrophy in-vivo. Utilizing a co-transfection assay, we have also obtained data that suggest that the beta-PKC isozyme is in a pathway regulating transcription of the beta-MHC isogene. Beta adrenergic stimulation of the cultured cardiac myocytes also results in a modest degree of hypertrophy, however, this effect may be dependent upon myocyte contractile activity and may involve, at least in part, the non-muscle cells present in the culture system.

Influence of sodium intake on left ventricular structure in untreated essential hypertensives

Among the many factors that have been implicated in the pathogenesis of myocardial hypertrophy is a sodium effect. In the present study, the influence of dietary sodium, estimated by 24-h natriuresis, on left ventricular mass was assessed in 41 patients with mild essential hypertension who had never been treated. Posterior wall thickness and left ventricular mass, but not left ventricular internal diameter were directly correlated with 24-h natriuresis (r = 0.47 and 0.46; P less than 0.02 and 0.002, respectively). Stepwise multiple regression analysis confirmed that 24-h natriuresis was a determinant of left ventricular mass independently of sex, age, body weight, blood pressure and the duration of hypertension. These results suggest that dietary sodium may play a role in modulating left ventricular mass in untreated hypertensives.