Increased Heart Weight Research Articles

Exercise training inhibits left ventricular collagen upregulation in mice with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is estimated to affect 1:500, and is characterised by otherwise unexplained left ventricular (LV) hypertrophy, cardiomyocyte disarray, fibrosis, diastolic dysfunction, and ventricular arrhythmias. Historically, patients with HCM have been discouraged from participation in high intensity sports and exercise. However, the 2020 Sports Cardiology Guidelines recommend that patients with HCM should receive advice about exercise training (ET) based on individual risk assessment. To learn more about the effects of ET in HCM, we exposed mice carrying an HCM-causative sarcomere mutation (Myh6R403Q/+ (R403Q) mice) to high intensity interval training. Purpose To investigate the effect of exercise training on hypertrophic cardiomyopathy in mice. Methods R403Q mice were stratified to treadmill exercise (n=11) or sedentary behaviour (n=11). After 3 weeks, we induced HCM by giving CsA in the feed for 3 weeks, while the ET or sedentary behaviour continued for a total of 6 weeks. Each bout of treadmill running consisted of a 10-minute warm up, followed by 5 intervals of 8 minutes at high intensity (90% of VO2 max speed at week 0) and 2 minutes at medium intensity (60% of VO2 max speed at week 0). Every third day of the ET protocol we increased the high and medium intensity running speeds by 0.6 and 0.4 m/min, respectively. We performed echocardiography after 0, 3, and 6 weeks of the 6-week protocol. After completion of the protocol, we recorded lung and whole heart weight, and harvested LVs for molecular analyses. Results Confirming the expected HCM phenotype, R403Q mice that received CsA (R403Q SED+CsA) had a 1.3-fold increase in whole heart weight (p<0.0001), 1.5-fold increase in lung weight (p<0.001), and 2.4-fold increase in maximal left ventricular posterior wall (LVPW) thickness measured by echocardiography (p<0.0001) compared to sedentary wild type littermates given CsA (WT SED+CsA). Heart weight, lung weight, and maximum LVPW thickness were also increased 1.5- (p<0.0001), 1.6- (p<0.0001), and 2.0-(p<0.0001) fold, respectively, compared to R403Q not given CsA (R403Q SED-CsA). R403Q ET+CsA mice increased their running distance before exhaustion 2.0-fold compared to baseline (p=0.010), and ran 1.6-fold longer than R403Q SED+CsA (p=0.020). In R403Q ET+CsA mice, LV mRNA expression of Col1a2 was 51% (p=0.021), and Col3a1 49% (p=0.013) of R403Q SED+CsA expression levels. Compared to R403Q SED+CsA mice, exercise training did not affect heart weight, maximum LV posterior wall thickness or lung weight in R403Q ET+CsA mice. Conclusion Treadmill ET inhibited upregulation of LV collagen expression in mice with HCM, but did not affect hypertrophy. This could indicate that ET during early development of HCM attenuates development of fibrosis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF) and KG Jebsen Cardiac Research Center

Visnagin prevents isoproterenol-induced myocardial injury by attenuating oxidative stress and inflammation and upregulating Nrf2 signaling in rats.

Oxidative tissue injury and inflammatory responses play major roles in cardiovascular diseases and heart failure. Visnagin (VIS) is a natural bioactive component of Ammi visnaga, with promising radical scavenging and anti-inflammatory activities. This study explored the protective effect of VIS against isoproterenol (ISO)-induced acute myocardial injury and oxidative stress in rats. VIS was supplemented for 14 days, and the rats received ISO (100 mg/kg) twice at an interval of 24 h. ISO-induced myocardial injury was characterized by elevated serum CK-MB, LDH, and troponin-I associated with increased heart weightand several histopathological changes. ISO increased reactive oxygen species (ROS), malondialdehyde (MDA), NF-κB p65, TNF-α, IL-6, and decreased glutathione and antioxidant enzymes in rats' hearts. VIS prevented myocardial injury and ameliorated the cardiac function markers, ROS, MDA, NF-κB p65, and pro-inflammatory cytokines in ISO-intoxicated rats. In addition, VIS decreased Bax mRNA and caspases, and upregulated Nrf2, HO-1, Bcl-2, and PPARγ. Molecular docking simulations revealed the binding method of VIS to NF-κB, Keap1, and PPARγ. In conclusion, VIS protects against ISO-induced acute myocardial injury by attenuating oxidative tissue injury and reducing key inflammatory and apoptosis markers. In vivo and in silico results showed that activation of Nrf2/HO-1 signaling and PPARγ mediates the cardioprotective effect of VIS.

Abstract P151: Cardiovascular Effects Of Peritoneal Dialysis In The 5/6 Nephrectomy Rat Model

In the US more than 130,000 people are diagnosed with end stage renal disease (ESRD) each year. Of those only 3% receive a kidney transplant while the remaining 97% are reliant on dialysis for survival. Among dialysis patients, cardiovascular (CV) related events are the leading cause of death. Despite therapeutic advancements the continued CVD following the onset of dialysis poses an interesting clinical challenge that necessitates studies into the effects and effectiveness of dialysis. Furthermore, home dialysis, particularly peritoneal dialysis (PD), has been utilized increasingly in ESRD care (up 10% in 2018) thus the need to understand PD effects on the CV system is urgent. Based on clinical outcomes, we hypothesized that PD would have no effect on CV outcomes in chronic kidney disease (CKD). To study CKD, we performed 5/6 nephrectomy (5/6Nx) or sham surgery, on 10 week old male Sprague-Dawley rats. Peritoneal catheters were then implanted 6 weeks post-surgery and PD was initiated 2 days later in some of the 5/6Nx and sham animals (15ml [Baxter PD-2 2.5%] 1-hour dwell 3x/day for 9 days). Echocardiography was performed at baseline, 6-, and 7-weeks post-surgery. At week 7 pressure volume analysis was performed prior to serum and tissue collection. Statistical significance was determined by two-way ANOVA. 5/6Nx increased heart weight (5/6Nx 0.43±0.02 vs. Sham 0.34±0.01; p<0.05). PD had no effect on heart weight in sham rats, but attenuated the increase in 5/6Nx rats (5/6Nx 0.43±0.02 vs. 5/6Nx PD 0.40±0.01; p<0.05). 5/6Nx increased systolic blood pressure (5/6Nx 133.6±5.6 vs. Sham 111.1±5.9; p<0.05). PD had no effect on blood pressure in either sham or 5/6Nx rats. 5/6Nx increased cholesterol (5/6Nx 134.9±8.3 vs. Sham 104.3±11; p<0.05), but PD attenuated the rise in cholesterol in 5/6Nx rats (5/6Nx 134.9±8.3 vs. 5/6Nx PD 115.7±9; p<0.05), and greatly increased triglycerides (5/6Nx 65.6±11 vs. 5/6Nx PD 165.5±11.9; p<0.05). CV echocardiography parameters in sham animals and in 5/6Nx were unchanged by PD. These data combined suggests that PD may have little to no effects on some CV parameters while worsening others. These findings indicate more studies focused on the CV effects of dialysis are necessary to help improve outcomes in the ESRD population.

Mechanisms of Systolic Cardiac Dysfunction in PP2A, PP5 and PP2AxPP5 Double Transgenic Mice.

As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated transgenic mice with cardiac muscle cell-specific overexpression of PP2Acα (PP2A) and PP5 (PP5). For further studies we crossbred PP2A and PP5 mice to obtain PP2AxPP5 double transgenic mice (PP2AxPP5, DT) and compared them with littermate wild-type mice (WT) serving as a control. The mortality of DT mice was greatly enhanced vs. other genotypes. Cardiac fibrosis was noted histologically and mRNA levels of collagen 1α, collagen 3α and fibronectin 1 were augmented in DT. DT and PP2A mice exhibited an increase in relative heart weight. The ejection fraction (EF) was reduced in PP2A and DT but while the EF of PP2A was nearly normalized after β-adrenergic stimulation by isoproterenol, it was almost unchanged in DT. Moreover, left atrial preparations from DT were less sensitive to isoproterenol treatment both under normoxic conditions and after hypoxia. In addition, levels of the hypertrophy markers atrial natriuretic peptide and B-type natriuretic peptide as well as the inflammation markers interleukin 6 and nuclear factor kappa B were increased in DT. PP2A enzyme activity was enhanced in PP2A vs. WT but similar to DT. This was accompanied by a reduced phosphorylation state of phospholamban at serine-16. Fittingly, the relaxation times in left atria from DT were prolonged. In summary, cardiac co-overexpression of PP2A and PP5 were detrimental to animal survival and cardiac function, and the mechanism may involve dephosphorylation of important regulatory proteins but also fibrosis and inflammation.

Male and Female Rats Have Different Physiological Response to High-Fat High-Sucrose Diet but Similar Myocardial Sensitivity to Ischemia-Reperfusion Injury.

Prediabetes is a strong predictor of type 2 diabetes and its associated cardiovascular complications, but few studies explore sexual dimorphism in this context. Here, we aim to determine whether sex influences physiological response to high-fat high-sucrose diet (HFS) and myocardial tolerance to ischemia-reperfusion injury. Male and female Wistar rats were subjected to standard (CTRL) or HFS diet for 5 months. Then, ex-vivo experiments on isolated perfused heart model were performed to evaluate tolerance to ischemia-reperfusion injury. HFS diet induced fasting hyperglycemia and increased body fat percent to a similar level in both sexes. However, glucose intolerance was more pronounced in female HFS. Cholesterol was increased only in female while male displayed higher level of plasmatic leptin. We observed increased heart weight to tibia length ratio only in males, but we showed a similar decrease in tolerance to ischemia-reperfusion injury in female and male HFS compared with respective controls, characterized by impaired cardiac function, energy metabolism and coronary flow during reperfusion. In conclusion, as soon as glucose intolerance and hyperglycemia develop, we observe higher sensitivity of hearts to ischemia-reperfusion injury without difference between males and females.

Atg5 knockdown induces age-dependent cardiomyopathy which can be rescued by repeated remote ischemic conditioning.

Altered autophagy is implicated in several human cardiovascular diseases. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models and modifies autophagy signaling, but its effect in cardiomyopathy induced by gene manipulation has not been reported. To investigate the cardiac effects of chronically reduced autophagy as a result of Atg5 knockdown and assess whether RIC can rescue the phenotype. Atg5 knockdown was induced with tamoxifen for 14 days in cardiac-specific conditional Atg5 flox mice. Autophagy proteins and cardiac function were evaluated by Western blot and echocardiography, respectively. RIC was induced by cyclical hindlimb ischemia and reperfusion using a tourniquet. RIC or sham procedure was performed daily during tamoxifen induction and, in separate experiments, chronically 3 times per week for 8 weeks. Cardiac responses were assessed by end of the study. Cardiac-specific knockdown of Atg5 reduced protein levels by 70% and was associated with a significant increase in mTOR, a reduction of LC3-II and increased upstream autophagy proteins including LC3-I, P62, and Beclin. The changes in biochemical markers were associated with development of an age-related cardiomyopathy during the 17-month follow-up indicated by increased heart weight body weight ratio, progressive decline in cardiac function, and premature death. RIC increased cardiac ATG5 and rescued some of the Atg5 knockdown-induced cardiomyopathy phenotype and associated morphological remodeling. We conclude that cardiac-specific Atg5 knockdown leads to the development of age-related cardiomyopathy. RIC reverses the molecular and structural phenotype when administered both acutely and chronically.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00395-021-00888-2.

Gastrodin Exerts Cardioprotective Action via Inhibition of Insulin-Like Growth Factor Type 2/Insulin-Like Growth Factor Type 2 Receptor Expression in Cardiac Hypertrophy.

Pathological cardiac hypertrophy is commonly associated with an upregulation of fetal genes, fibrosis, cardiac dysfunction, and heart failure. Previous studies have demonstrated that gastrodin (GAS) exerts cardioprotective action in the treatment of cardiac hypertrophy. However, the mechanism by which GAS protects against cardiac hypertrophy is yet to be elucidated. A mouse model of myocardial hypertrophy was established using an angiotensin II (Ang II) induction. GAS (5 or 50 mg/kg/d) was orally administered every day starting 7 days prior to the Ang II infusion combined with sham-operated controls. Heart samples from each group were collected for RNA sequencing. Using bioinformatics analysis, the key differentially expressed genes (DEGs) that are involved in reversing cardiac function were identified. Through bioinformatics analysis, the key DEGs that are involved in GAS’s inhibition of Ang II-induced abnormal gene expression within the heart were identified. This was further validated using quantitative real-time PCR and Western blotting in neonatal rat cardiomyocytes (NRCMs). Oral administration of GAS significantly suppressed the Ang II-induced increase in heart size and heart weight to body weight. Furthermore, pretreatment of the NRCMs with GAS led to a dose-dependent inhibition of Ang II-induced increases in Nppb mRNA expression. We identified 620 upregulated and 87 downregulated Ang II-induced DEGs II, among which the expression patterns of 58 and 146 genes were inverted by low-dose and high-dose GAS, respectively. These inverted DEGs were found to be mainly enriched in the biological processes of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism, and positive regulation of cell cycle. Among them, the insulin-like growth factor type 2 (Igf2) gene, which was found to be highly reversed and downregulated by GAS, served as a core gene linking energy metabolism, immune regulation, and systemic development. Subsequent functional verification demonstrated that IGF2, and its receptor IGF2R, is one of the targets of GAS that helps protect against cardiac hypertrophy. Taken together, we have identified, for the first time, IGF2/IGF2R as a potential target influenced by GAS in the prevention of cardiac hypertrophy.

Cardiac Dysfunction in a Mouse Vascular Dementia Model of Bilateral Common Carotid Artery Stenosis.

Background: Cardiac function is associated with cognitive function. Previously, we found that stroke and traumatic brain injury evoke cardiac dysfunction in mice. In this study, we investigate whether bilateral common carotid artery stenosis (BCAS), a model that induces vascular dementia (VaD) in mice, induces cardiac dysfunction.Methods: Late-adult (6–8 months) C57BL/6J mice were subjected to sham surgery (n = 6) or BCAS (n = 8). BCAS was performed by applying microcoils (0.16 mm internal diameter) around both common carotid arteries. Cerebral blood flow and cognitive function tests were performed 21–28 days post-BCAS. Echocardiography was conducted in conscious mice 29 days after BCAS. Mice were sacrificed 30 days after BCAS. Heart tissues were isolated for immunohistochemical evaluation and real-time PCR assay.Results: Compared to sham mice, BCAS in mice significantly induced cerebral hypoperfusion and cognitive dysfunction, increased cardiac hypertrophy, as indicated by the increased heart weight and the ratio of heart weight/body weight, and induced cardiac dysfunction and left ventricular (LV) enlargement, indicated by a decreased LV ejection fraction (LVEF) and LV fractional shortening (LVFS), increased LV dimension (LVD), and increased LV mass. Cognitive deficits significantly correlated with cardiac deficits. BCAS mice also exhibited significantly increased cardiac fibrosis, increased oxidative stress, as indicated by 4-hydroxynonenal and NADPH oxidase-2, increased leukocyte and macrophage infiltration into the heart, and increased cardiac interleukin-6 and thrombin gene expression.Conclusions: BCAS in mice without primary cardiac disease provokes cardiac dysfunction, which, in part, may be mediated by increased inflammation and oxidative stress.

KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy

BackgroundCardiovascular diseases have become the leading cause of death worldwide, and cardiac hypertrophy is the core mechanism underlying cardiac defect and heart failure. However, the underlying mechanisms of cardiac hypertrophy are not fully understood. Here we investigated the roles of Kallikrein 11 (KLK11) in cardiac hypertrophy.MethodsHuman and mouse hypertrophic heart tissues were used to determine the expression of KLK11 with quantitative real-time PCR and western blot. Mouse cardiac hypertrophy was induced by transverse aortic constriction (TAC), and cardiomyocyte hypertrophy was induced by angiotensin II. Cardiac function was analyzed by echocardiography. The signaling pathway was analyzed by western blot. Protein synthesis was monitored by the incorporation of [3H]-leucine. Gene expression was analyzed by quantitative real-time PCR.ResultsThe mRNA and protein levels of KLK11 were upregulated in human hypertrophic hearts. We also induced cardiac hypertrophy in mice and observed the upregulation of KLK11 in hypertrophic hearts. Our in vitro experiments demonstrated that KLK11 overexpression promoted whereas KLK11 knockdown repressed cardiomyocytes hypertrophy induced by angiotensin II, as evidenced by cardiomyocyte size and the expression of hypertrophy-related fetal genes. Besides, we knocked down KLK11 expression in mouse hearts with adeno-associated virus 9. Knockdown of KLK11 in mouse hearts inhibited TAC-induced decline in fraction shortening and ejection fraction, reduced the increase in heart weight, cardiomyocyte size, and expression of hypertrophic fetal genes. We also observed that KLK11 promoted protein synthesis, the key feature of cardiomyocyte hypertrophy, by regulating the pivotal machines S6K1 and 4EBP1. Mechanism study demonstrated that KLK11 promoted the activation of AKT-mTOR signaling to promote S6K1 and 4EBP1 pathway and protein synthesis. Repression of mTOR with rapamycin blocked the effects of KLK11 on S6K1 and 4EBP1 as well as protein synthesis. Besides, rapamycin treatment blocked the roles of KLK11 in the regulation of cardiomyocyte hypertrophy.ConclusionsOur findings demonstrated that KLK11 promoted cardiomyocyte hypertrophy by activating AKT-mTOR signaling to promote protein synthesis.

FC 064A RENAL-CARDIO INFLAMMATORY AXIS MEDIATES CARDIAC DYSFUNCTION IN CKD VIA IL-33-ST2: A NOVEL MECHANISM

Abstract Background and Aims We developed a swine model of chronic kidney disease (CKD) that also display cardiac abnormalities associated with heart failure (HF). Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with CKD. Interleukin (IL)-33 is a tissue-derived nuclear cytokine from the IL family. IL-33 constitutively expressed but upregulated and released after cellular damage or necrotic cell death, acting as a pro-inflammatory cytokine. We hypothesize that IL-33 plays a prominent mechanistic role in renal-cardio pathophysiology in CKD. Method We induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. We developed a renally-targeted biopolymer-fused peptide inhibitor of nuclear-factor kappa (NF-k)B (ELP-p50i) and show it blocks NFkB activity in vitro and in vivo. NF-kB is a key pro-inflammatory transcription factor upregulated in CKD and closely interacts with IL-33. Pigs were observed for 6 weeks, renal (multi-detector CT) and cardiac structure and function (echo) were quantified, then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later. Blood was collected to measure circulating TNF-α, IL-33 and its specific decoy receptor soluble (s) ST2 (ELISA). Heart weights were measured after euthanasia, and renal and cardiac expression of ST2 and morphometric analyses were performed. Results Loss of renal function in CKD was accompanied by increased heart weight, left ventricular (LV) hypertrophy, diastolic dysfunction, abnormal LV strain, renal/cardiac fibrosis, circulating TNF-α, IL-33 but unchanged sST2, and increased renal/cardiac ST2 expression. Most of these changes were improved after intra-renal ELP-p50i and accompanied by augmented sST2, suggesting that inhibition of renal inflammation can attenuate cardiac abnormalities via augmented clearance of IL-33 (Figure). Conclusion Our study supports a prominent role for renal inflammation as a driving force for precursors of HF in CKD, proposing a renal-cardio inflammatory axis possibly mediated by NF-kB-TNF-α-IL-33/ST2 interactions. TNF-α can stimulate IL-33 as IL33 can activate NF-kB and TNF-α, extending this inflammatory loop in both the kidney and heart. We show that a translational renal anti-inflammatory strategy via targeted inhibition of renal NFkB inhibits this axis and improves renal and cardiac function, which may guide to new treatments targeting renal inflammation in CKD.

Study on Heart Measurements of the People between the Age 20-40 Years Present to the Teaching Hospital Colombo North – Post Mortem Study

Introduction: Presence of an enlarged heart provides a basis for determination of the cause and mechanisms of death. Gender, physical activity, and Body Mass Index (BMI) may affect the sizeof organs. Knowledge on such normal variations is needed in order to recognize theabnormalities.Objectives- This research was conducted to study the dimensions of the heart(heart weight, left ventricular thickness and valvular circumferences) among the young adult healthy deceased autopsies and evaluate their association with differentvariables.Methods: It was a descriptive cross-sectional study and 20-40 years of age healthy, young, adult, males and females in equal numbers who had died suddenly were studied by considering the inclusion and exclusion criteria. Details of the past history and the measurements were enteredinto a proforma and the anonymous data wereused for analysis.Results: The study revealed that the mean values of the heartweight was 280.52g (SD+/- 42.60), it was 293.94g (SD+/-39.29) for males and 267.10g (SD+/-42.64) for females. There was no significant association of heart weight with gender (P= 0.46410). There was a significant association between BMI and the heart weight of the females (P= 0.0387), no such association for left ventricular wall thickness. Further, there was a significant difference of the tricuspid valve circumference among two genders and the values were 11.6cm (SD+/-0.82) for males and 10.7cm (SD+/-0.6) forfemales.Conclusions: Majority of the findings was consistent with the findings of the studies globally on Caucasians. Increased body mass index was significantly associated with increased heart weight among females which could probably be explained as a consequence of increased epicardial fat since there was no such association for left ventricular wallthickness.

Study on Heart Measurements of the People between the age 20-40 Years Present to the Teaching Hospital Colombo North – Post mortem Study

Introduction: Presence of an enlarged heart provides a basis for determination of the cause and mechanisms of death. Gender, physical activity, and Body Mass Index (BMI) may affect the size of organs. Knowledge on such normal variations is needed in order to recognize the abnormalities.Objectives- This research was conducted to study the dimensions of the heart(heart weight, left ventricular thickness and valvular circumferences) among the young adult healthy deceased autopsies and evaluate their association with different variables.Methods: It was a descriptive cross-sectional study and 20-40 years of age healthy, young, adult, males and females in equal numbers who had died suddenly were studied by considering the inclusion and exclusion criteria. Details of the past history and the measurements were entered into a proforma and the anonymous data were used for analysis.Results: The study revealed that the mean values of the heart weight was 280.52g (SD+/- 42.60), it was 293.94g (SD+/-39.29) for males and 267.10g (SD+/-42.64) for females. There was no significant association of heart weight with gender (P= 0.46410). There was a significant association between BMI and the heart weight of the females (P= 0.0387), no such association for left ventricular wall thickness. Further, there was a significant difference of the tricuspid valve circumference among two genders and the values were 11.6cm (SD+/-0.82) for males and 10.7cm (SD+/-0.6) for females.Conclusions: Majority of the findings was consistent with the findings of the studies globally on Caucasians. Increased body mass index was significantly associated with increased heart weight among females which could probably be explained as a consequence of increased epicardial fat since there was no such association for left ventricular wall thickness.

Effects of KY-903, a Novel Tetrazole-Based Peroxisome Proliferator-Activated Receptor γ Modulator, in Male Diabetic Mice and Female Ovariectomized Rats.

Peroxisome proliferator-activated receptor γ (PPARγ) modulators are expected to exert anti-diabetic effects without PPARγ-related adverse effects, such as fluid retention, weight gain, and bone loss. The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. These effects were similar to those of pioglitazone. Pioglitazone, but not KY-903, increased adipose tissue and heart weights. In pre-adipocytes (3T3-L1), KY-903, in contrast to pioglitazone, increased adiponectin mRNA levels without adipocyte differentiation, indicating anti-diabetic effects via adiponectin without adipogenesis. In ovariectomized rats fed a high-fat diet (OVX/HFD), KY-903 and pioglitazone decreased plasma triglyceride and non-esterified fatty acid levels and increased adiponectin levels, indicating insulin sensitization via adiponectin. KY-903 reduced body weight gain and adipose tissue weight, while pioglitazone increased heart weight and markedly reduced bone mineral density. In mesenchymal stem cell-like ST2 cells, KY-903 slightly reduced osteoblast differentiation without adipocyte differentiation, while pioglitazone markedly reduced it with adipocyte differentiation. In conclusion, KY-903 is a novel PPARγ modulator that exerts anti-diabetic effects without body weight gain or cardiac hypertrophy in diabetic mice and anti-obesity effects with minor bone loss in OVX/HFD, possibly due to increases in adiponectin levels without adipogenesis.

Cinacalcet as a surrogate therapy for diabetic cardiomyopathy in rats through AMPK-mediated promotion of mitochondrial and autophagic function

Decreased activity of AMP-activated protein kinase (AMPK) is implicated in the pathogenesis of diabetic cardiomyopathy (DCM). Recent evidence suggests a crosstalk between cinacalcet and AMPK activation. This study investigated the effects of cinacalcet on cardiac remodeling and dysfunction in type 2 diabetic rats (T2DM). High fat diet for 4 weeks combined with single intraperitoneal injection of streptozotocin (30 mg/kg) was used to induce type 2 diabetes in rats. Diabetic rats were either orally treated with vehicle, 5 or 10 mg/kg cinacalcet for 4 weeks. Control rats were fed standard chow diet and intraperitoneally injected with citrate buffer. T2DM rats showed lower body weight (BW), hyperglycemia and dyslipidemia, along with increased heart weight (HW) and HW/BW ratio. Masson's trichrome stained cardiac sections revealed massive fibrosis in T2DM rats. There were increased TGF-β1 and hydroxyproline levels, coupled with up-regulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in hearts of T2DM rats. These alterations were associated with redox imbalance and impaired cardiac functions. Decreased phosphorylation of AMPK at threonine172 residue was found in T2DM hearts. Cinacalcet for 4 weeks significantly activated AMPK and alleviated cardiac remodeling and dysfunction in a dose-dependent manner, without affecting blood glucose, serum calcium and phosphorus levels. Cinacalcet increased the mitochondrial DNA content, and expressions of PGC-1α, UCP-3, beclin-1 and LC3-II/LC3-I ratio. Cinacalcet decreased the pro-apoptotic Bax, while increased the anti-apoptotic Bcl-2 in cardiac tissue of T2DM rats. These findings might highlight cinacalcet as an alternative therapy to combat the development and progression of DCM.

Contribution of sympathetic activation to antihypertrophic memory after regression of exercise-induced physiological myocardial hypertrophy in mice

To investigate whether anti-hypertrophic memory exists after regression of exercise-induced physiological myocardial hypertrophy (PMH) and explore the contribution of sympathetic activation to hypertrophic memory formation. Seventy-two mice were randomized equally into 6 groups, including sedentary sham-operated group, exercise hypertrophic preconditioning (EHP) + sham operation group, bisoprolol (an adrenergic β1 receptor blocker) + EHP + sham operation group (biso+Exe+Sham group), sedentary group with transverse aortic constriction (TAC) (Sed+TAC group), EHP+ TAC group (Exe+TAC group), and bisoprolol+EHP+TAC group (biso+Exe+TAC group). The mice in the EHP groups were subjected to 3 weeks of swimming training, and in the bisoprolol groups, bisoprolol was administered by gavage once daily from two days before till the end of the training. One week after the training, TAC or sham surgery was performed. Echocardiography and hemodynamic measurements were performed to evaluate cardiac function of the mice, and the myocardial tissues were examined histologically to detect cardiac remodeling. Compared with the sedentary group, the mice receiving 3 weeks of swimming training had significantly increased heart weight to body weight ratio (HW/BW), HW to tibia length ratio (HW/TL), and the cross-sectional area of the cardiomyocytes (P < 0.05). One week after the training, exercise-induced PMH rapidly diminished and both HW/BW and HW/TL recovered the baseline levels. Treatment with bisoprolol obviously prevented the occurrence of PMH. Four weeks after TAC, the left ventricular posterior wall thickness, HW/BW, HW/TL, left ventricular end diastolic pressure and cross-sectional area of cardiomyocytes were all significantly lower (P < 0.05) while the left ejection fraction and maximal change rate of left ventricular pressure were significantly higher (P < 0.05) in Exe + TAC group than in Sed + TAC group. No significant difference was found in these parameters between biso + Exe + TAC group and Sed + TAC group. Anti-hypertrophic memory exists even after the regression of exercise-induced PMH, which may be attributed to the activation of sympathetic nervous system during exercise.

Effects of SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone on fluid retention in type 2 diabetic mice with NASH

Several antidiabetic agents, including thiazolidinediones and sodium-glucose cotransporter (SGLT) 2 inhibitors, attenuate the symptoms of nonalcoholic steatohepatitis (NASH). However, thiazolidinediones have serious side effects such as fluid retention and increased risk of congestive heart failure. We examined the effects of SGLT2 inhibitor ipragliflozin, pioglitazone, and ipragliflozin + pioglitazone on fluid retention in type 2 diabetic mice with NASH. Four-week repeated administration of pioglitazone caused significant increases in heart weight (31% increase in 30 mg/kg pioglitazone-treated group compared to vehicle-treated group) concomitant with fluid retention, as estimated by a decrease in plasma osmolality and increase in water intake/urine volume ratio. In addition, pioglitazone significantly increased (by 1.5 to 2-fold) mRNA expression of α, β, and γ subtypes of ENaC and AQP2 and 3 subtypes in the renal medulla. Thus, pioglitazone-induced fluid retention may arise from enhanced reabsorption of sodium and water associated with increased expression of these channels in the kidney. In contrast, ipragliflozin alone did not induce these symptoms and did not affect ENaC or AQP expression. Combination treatment with ipragliflozin + pioglitazone attenuated these symptoms by ipragliflozin-induced osmotic diuresis. These findings demonstrate that treatment with ipragliflozin monotherapy or coadministered with pioglitazone may be a potential therapeutic option for the treatment of type 2 diabetes with NASH without fluid retention as a side effect.

Upregulated Angiogenesis Is Incompetent to Rescue Dilated Cardiomyopathy Phenotype in Mice.

Dilated cardiomyopathy (DCM) is characterized by pathologic cardiac remodeling resulting in chambers enlargement and impaired heart contractility. Previous reports and our in-silico analysis support the association of DCM phenotype and impaired tissue angiogenesis. Here, we explored whether the modulation in cardiac angiogenesis partly intervenes or rescues the DCM phenotype in mice. Here, a DCM mouse model [α-tropomyosin 54 (α-TM54) mutant] was crossbred with microRNA-210 transgenic mice (210-TG) to develop microRNA-210 (miR-210) overexpressing α-TM54 mutant mice (TMx210). Contrary to wild-type (WT) and 210-TG mice, a significant increase in heart weight to body weight ratio in aged mixed-gender TMx210 and DCM mice was recorded. Histopathological analysis revealed signs of pathological cardiac remodeling such as myocardial disarray, myofibrillar loss, and interstitial fibrosis in DCM and TMx210 mice. Contrary to WT and DCM, a significant increase in angiogenic potential was observed in TMx210 and 210-TG mice hearts which is reflected by higher blood vessel density and upregulated proangiogenic vascular endothelial growth factor-A. The echocardiographic assessment showed comparable cardiac dysfunction in DCM and TMx210 mice as compared to WT and 210-TG. Overall, the present study concludes that miR-210 mediated upregulated angiogenesis is not sufficient to rescue the DCM phenotype in mice.

Characterisation of hypertensive heart disease: pathological insights from a sudden cardiac death cohort to inform clinical practice.

Hypertensive heart disease refers to changes in the myocardium that result from hypertension. The relationship between hypertensive heart disease and sudden cardiac death is well established, but there are few pathological studies. We examined the clinical and pathological features of hypertensive heart disease in sudden cardiac death victims from a national cardiovascular pathology registry. We investigated 5239 cases of sudden cardiac death between 1994 and 2018. Hearts were examined by two expert cardiac pathologists. Diagnostic criteria included history of hypertension, increased heart weight and left ventricular wall thickness in the absence of other causes. Collagen was quantified using picrosirius red staining and imaging software. Of 75 sudden cardiac death cases due to hypertensive heart disease (age at death: 54 ± 16 years; 56% males), 56 (75%) reported no prior cardiac symptoms. Thirty-four (45%) recorded a BMI ≥ 30. Only two (2.7%) had hypertensive heart disease diagnosed antemortem. Four (5%) were diagnosed clinically with hypertrophic cardiomyopathy, but lacked myocyte disarray at autopsy. All hearts showed concentric left ventricular hypertrophy and myocyte hypertrophy. Fibrosis was identified microscopically in 59 cases (81%). The posterior left ventricular wall showed the greatest increase in the percentage of collagen in hypertensive diseased hearts compared to controls (25.2% vs 17.9%, p = 0.034). Most sudden deaths due to hypertensive heart disease occur without prior cardiac symptoms; thus, clinical risk stratification is challenging. Hypertensive heart disease can be misdiagnosed in life as hypertrophic cardiomyopathy which has major implications for relatives. Pathologists require a history of hypertension and histology for a definitive diagnosis of hypertensive heart disease.

GPR39 promotes cardiac hypertrophy by regulating the AMPK-mTOR pathway and protein synthesis.

Hypertrophic growth of the cardiomyocytes is one of the core mechanisms underlying cardiac hypertrophy. However, the mechanism underlying cardiac hypertrophy remains not fully understood. Here we provided evidence that G protein-coupled receptor 39 (GPR39) promotes cardiac hypertrophy via inhibitingAMP-activated protein kinase (AMPK)signaling. GRP39 expression is overexpressed in hypertrophic hearts of humans and transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice. In neonatal cardiomyocytes, adenovirus-mediated overexpression of GPR39 promoted angiotensin II-induced cardiac hypertrophy, while GPR39 knockdown repressed hypertrophic response. Adeno-associated virus 9-mediated knockdown of GPR39 suppressed TAC-induced decline in fraction shortening and ejection fraction, increase in heart weight and cardiomyocyte size, as well as overexpression of hypertrophic fetal genes. A mechanism study demonstrated that GPR39 repressed the activation of AMPK to activate the mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase β-1 (S6K1), subsequently promoted de novo protein synthesis. Inhibition of mTOR with rapamycin blocked the effects of GPR39 overexpression on protein synthesis and repressed cardiac hypertrophy. Collectively, our findings demonstrated that GPR39 promoted cardiac hypertrophy via regulating the AMPK-mTOR-S6K1 signaling pathway, and GRP39 can be targeted for the treatment of cardiac hypertrophy.

PHD Finger Protein 19 Promotes Cardiac Hypertrophy via Epigenetically Regulating SIRT2

Epigenetic 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.