Increased Heart Mass Research Articles

ВЛИЯНИЕ СКАРМЛИВАНИЯ КУКУРУЗНОГО ЭКСТРАКТА НА РАЗВИТИЕ ВНУТРЕННИХ ОРГАНОВ ЦЫПЛЯТ МЯСНОГО НАПРАВЛЕНИЯ ПРОДУКТИВНОСТИ

The purpose of research is to study the effect of feeding complete feed (CF) with 6.5 % corn extract and 6.2 % mixture of corn extract and perlite on productivity, ration conversion and development of internal organs of broiler chickens. From the fourth day of cultivation, three groups of 38 heads of young birds were formed according to the principle of pair-analogues. In accordance with the scheme of the experiment, the birds from the 1st (control) group were given complete feed (CF) without the inclusion of additives. Corn extract (CE) was added to the complete mixed feed for poultry of the 2nd (experimental) group in the amount of 6.5 % by weight of the feed. The diet for chickens of the 3rd group included 6.2 % of a mixture of corn extract and perlite (in a ratio of 3.42 : 1). Feeding 6.5 % corn extract resulted in a 1.8 % increase in heart mass; a significant decrease in liver weight by 12.7 % (p < 0.05), in contrast to the group of birds that received complete feed without additives. Also, when feeding a mixture of 6.2 % corn extract and perlite, there was a trend towards an increase in heart weight by 2.5 % and a decrease in liver weight by 15.3 % (p < 0.05), relative to the control group. The pH values of the blind processes were in the range of 6.23–6.30, which is the biological norm. The inclusion of 6.5 % corn extract and a mixture of 6.2 % corn extract and perlite in a ratio of 3.42 : 1 by weight of the feed into complete mixed feeds can help increase the growth intensity of meat poultry, while not adversely affecting the growth and development of internal organs.

Abstract Tu069: Development of a Novel Biallelic, Haploinsufficient Mouse Model of MYBPC3 Related Hypertrophic Cardiomyopathy

Background: No current animal models re-capitulate MyBP-c haploinsufficiency and hypertrophic cardiomyopathy (HCM) observed in patients with heterozygous MYBPC3 truncating variants, the most common genetic cause of HCM. We recently identified a hypomorphic (partial) loss of function MYBPC3 variant that increases disease severity in HCM patients when combined with an MYBPC3 truncating variant. Hypothesis: Additive effects from a hypomorphic loss of function MYBPC3 variant observed in human HCM will result in MyBP-c protein haploinsufficiency and HCM in a biallelic murine model. Methods: To test MYBPC3 dose effects, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were first derived from an HCM patient with biallelic hypomorphic and complete loss of function variants in MYBPC3 . We then generated Mybpc3 knock out (Mybpc3 KO ) and hypomorphic knock in (Mybpc3 KI ) alleles in mice. Control (Mybpc3 +/+ ), monoallelic, and biallelic mice and iPSC-CMs were characterized with morphometric measurements, echocardiography, mass spectroscopy, and RNA sequencing. Results: Biallelic iPSC-CMs demonstrated haploinsufficiency not present in heterozygous models through dose reduction in MYBPC3 protein (Fig 1A). Similarly, biallelic Mybpc3 KI/KO mice had a reduction in Mybpc3 transcripts (62±3%, p<0.001) with 43±11%% reduction in MyBP-c protein (Fig 1B) and cardiac hypertrophy (10±5% increase in heart mass, p=0.002, Fig 1C). Conclusions: Graded reduction in Mybpc3 transcripts in a biallelic mouse model results in MyBP-c haploinsufficiency similar to that observed in HCM patients. Corresponding hypertrophy establishes this approach as a clinically relevant, novel model of MYBPC3 HCM.

Abstract Tu106: Cardiomyocyte knockout of Ceramide Synthase 5 protects against metabolic cardiomyopathy and obesity in mice

Introduction: The prevalence of metabolic cardiomyopathy in the absence of hypertension is on the rise. Ceramide Synthase 5 (CerS5) has been implicated in the pathophysiology of this cardiomyopathy. Hypothesis: Depletion of cardiomyocyte CerS5 protects against metabolic cardiomyopathy. Methods: Inducible cardiomyocyte-specific CerS5 knockout (CerS5 cKO) mice were generated and placed on a milk-fat diet (HFD) or control diet (CD) for 18 weeks along with control (Myh6-MCM) mice (n=6-11/group). Diet-induced metabolic syndrome was monitored through weekly weight measurements, glucose and insulin tolerance tests, and blood plasma collection for Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Echocardiography and systemic blood pressure were analyzed at baseline and end of diet. Hearts were assessed for hypertrophy, targeted lipidomics, untargeted metabolomics, and markers associated with cardiometabolic pathophysiology. Results: CerS5 cKO mice on HFD exhibited protection from increased heart mass (Fig. 1A-B, KO:6.1±0.2 vs. control:7.6±0.3 mg/mm, P=0.0001), cardiomyocyte hypertrophy (Fig. 1C, KO:252.6±8.1 vs. control:315.2±14.0 µm 2 , P=0.0084), and reduced ejection fraction (Fig. 1D, KO:65.8±3.0 vs. control:51.7±2.4 %, P=0.0047) compared to controls on HFD. Systemic systolic (SBP) and diastolic (DBP) blood pressures at 18 weeks on diet did not vary between groups (Fig. 1E-F). KO mice on HFD also showed protection from metabolic comorbidities, including obesity (Fig. 2A-B, KO:26.1±1.1 vs. control:30.7±1.7 g, P=0.0192), increased HOMA-IR (Fig. 2C-D, KO:12.6±3.0 vs. control:26.0±3.4, P=0.0015), reduced glucose and insulin insensitivity (Fig. 2E-L) compared to control on HFD. This phenotype was associated with reduced CerS5-derived sphingomyelin C14 (Fig. 3A, KO:8.9±1.4 vs. control:164.5±13.5 pmol/mg protein, P=0.0082), C16 (Fig. 3A, KO:168.0±16.8 vs. control:812.4±287.6 pmol/mg protein, P<0.0001) and ceramide C16 (Fig. 3B, KO:34.6±6.2 vs. control:112.7±16.1 pmol/mg protein, P<0.0001), in the heart. Excessive autophagy (Fig. 3C-D) was observed in the hearts of control mice on HFD, but not in the KO mice on HFD. The heart metabolome of CerS5 cKO mice on HFD was more similar to control mice on CD than control mice on HFD (Fig. 3E). Conclusions: Cardiomyocyte CerS5 depletion is crucial in maintaining cardiac and systemic metabolic homeostasis in mice with cardiometabolic pathophysiology. Excessive autophagy is a novel mechanism through which this may occur.

MicroRNA205: A Key Regulator of Cardiomyocyte Transition from Proliferative to Hypertrophic Growth in the Neonatal Heart.

The mammalian myocardium grows rapidly during early development due to cardiomyocyte proliferation, which later transitions to cell hypertrophy to sustain the heart's postnatal growth. Although this cell transition in the postnatal heart is consistently preserved in mammalian biology, little is known about the regulatory mechanisms that link proliferation suppression with hypertrophy induction. We reasoned that the production of a micro-RNA(s) could serve as a key bridge to permit changes in gene expression that control the changed cell fate of postnatal cardiomyocytes. We used sequential expression analysis to identify miR205 as a micro-RNA that was uniquely expressed at the cessation of cardiomyocyte growth. Cardiomyocyte-specific miR205 deletion animals showed a 35% increase in heart mass by 3 months of age, with commensurate changes in cell cycle and Hippo pathway activity, confirming miR205's potential role in controlling cardiomyocyte proliferation. In contrast, overexpression of miR205 in newborn hearts had little effect on heart size or function, indicating a complex, probably redundant regulatory system. These findings highlight miR205's role in controlling the shift from cardiomyocyte proliferation to hypertrophic development in the postnatal period.

The Elusive Hypertrophy of the Python Heart.

The Burmese python, one of the world's largest snakes, has reached celebrity status for its dramatic physiological responses associated with digestion of enormous meals. The meals elicit a rapid gain of mass and function of most visceral organs, particularly the small intestine. There is also a manyfold elevation of oxygen consumption that demands the heart to deliver more oxygen. It therefore made intuitive sense when it was reported that the postprandial response entailed a 40% growth of heart mass that could accommodate a rise in stroke volume. Many studies, however, have not been able to reproduce the 40% growth of the heart. We collated published values on postprandial heart mass in pythons, which include several instances of no change in heart mass. On average, the heart mass is only 15% greater. The changes in heart mass did not correlate to the mass gain of the small intestine or peak oxygen consumption. Hemodynamic studies show that the rise in cardiac output does not require increased heart mass but can be fully explained by augmented cardiac filling and postprandial tachycardia. Under the assumption that hypertrophy is a contingent phenomenon, more recent experiments have employed two interventions such as feeding with a concomitant reduction in hematocrit. The results suggest that the postprandial response of the heart can be enhanced, but the 40% hypertrophy of the python heart remains elusive.

Abstract P2064: A Specialized Centrosome-Proteasome Axis Mediates Proteostasis And Influences Cardiac Hypertrophy

Mature cardiomyocytes (CMs) lack centrosomes. Instead, centriolar and satellite proteins redistribute into specialized perinuclear organelle-like compartments, where they likely serve multifunctional roles, e.g., in organizing microtubules and establishing localized clearance of aggregated/misfolded proteins via the ubiquitin-proteasome system (UPS). Taxilin-beta (Txlnb) is a CM-enriched protein that localizes perinuclear and belongs to the family of taxilin proteins, which are centrosomal proteins that have been implicated in protein quality control. We hypothesize that Txlnb plays key roles maintaining specialized centrosomal-proteasomal crosstalk in CMs. We first examined proteostatic roles for Txlnb in neonatal rat CMs treated with phenylephrine and found that Txlnb overexpression coordinately increased protein synthesis and proteasome activity, while decreasing ubiquitin-protein conjugate accumulation. We generated Txlnb knockout (Txlnb-KO) mice, which show robust accumulation of ubiquitinated proteins and decreased 26SB5 proteasome activity in heart tissues, as well as lower cardiac mass with aging. To test if Txlnb influences proteotoxic UPS dysfunction, we crossed Txlnb-KO mice to Cryab-R120G transgenic mice, a model of severe cardiac proteotoxicity with progression to heart failure and early death. Loss of Txlnb resulted in worsening of heart failure, evidenced by lower ejection fractions in Txlnb-KO/Cryab-R120G mice versus Cryab-R120G littermates. By contrast, AAV-mediated Txlnb overexpression in Cryab-R120G mice resulted in only slight reduction in myocardial wall thickness but was overall insufficient to slow heart failure progression. To test if Txlnb influences hypertrophic UPS dysfunction, Txlnb-KO and wildtype (WT) mice were subjected to cardiac pressure-overload induced by transverse aortic constriction (TAC). At 6-weeks post-TAC, Txlnb-KO mice showed reduced ejection fraction, increased heart mass, and elevated accumulation of ubiquitinated proteins, relative to WT mice. Together, these data provide initial evidence connecting Txlnb to proteostatic functions in cardiomyocytes, hinting at the potential importance of functional bridging between specialized centrosomes and UPS in CMs.

Ferulic acid attenuates high glucose-induced MAM alterations via PACS2/IP3R2/FUNDC1/VDAC1 pathway activating proapoptotic proteins and ameliorates cardiomyopathy in diabetic rats

BackgroundDiabetic cardiomyopathy (DCM) is one of the severe complications of diabetes with no known biomarkers for early detection. Mitochondria-associated endoplasmic reticulum membranes (MAM) are less studied subcellular targets but an emerging area for exploration in metabolic disorders including DCM. We herein studied the role of MAMs and downstream mitochondrial functions in DCM. We also explored the efficacy of ferulic acid (FeA) against DCM via modulation of MAM and its associated signaling pathway. MethodsThe H9c2 cardiomyoblast cells were incubated with high concentration (33 mM) of d-glucose for 48 h to create a high glucose ambience in vitro. The expression of various critical proteins of MAM, mitochondrial function, oxidative phosphorylation (OxPhos) and the genesis of apoptosis were examined. The rats fed with high fat/high fructose/streptozotocin (single dose, i.p.) were used as a diabetic model and analyzed the insulin resistance and markers of cardiac hypertrophy and apoptosis. ResultsHigh glucose conditions caused the upregulation of MAM formation via PACS2, IP3R2, FUNDC1, and VDAC1 and decreased mitochondrial biogenesis, fusion and OxPhos. The upregulation of mitochondria-driven SMAC-HTRA2-ARTS-XIAP apoptosis and other cell death pathways indicate their critical roles in the genesis of DCM at the molecular level. The diabetic rats also showed cardiomyopathy with increased heart mass index, TNNI3K, troponin, etc. FeA effectively prevented the high glucose-induced MAM alterations and associated cellular anomalies both in vitro and in vivo. ConclusionHigh glucose-induced MAM distortion and subsequent mitochondrial dysfunctions act as the stem of cardiomyopathy. MAM could be explored as a potential target to treat diabetic cardiomyopathy. Also, the FeA could be an attractive nutraceutical agent for diabetic cardiomyopathy.

PSUN136 CCN5/WISP2 gene deficiency improves insulin sensitivity and glucose tolerance in diet-induced obesity, especially in male mice

Abstract CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 promotes the proliferation and survival of pancreatic β-cells leading to metabolic benefits [1]. Recently, the effects of CCN5 gene deficiency and ectopic, transgenic overexpression of CCN5 have been established. A systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance which are further exacerbated upon high-fat diet (HFD) feeding [2]. On the other hand, an adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes and increased heart mass but decreased fasting glucose levels [3]. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. In order to consolidate those findings and further establish the metabolic roles played by endogenous CCN5, we characterized CCN5 knockout mice fed in chow diet or 60% HFD. Unlike being reported [2], however, CCN5 knockout mice in our hands, both male and female, exhibited no significant change in lean/fat mass, insulin sensitivity, nor glucose tolerance when fed a chow diet, despite 2-5-fold elevations in serum insulin concentration. Upon HFD feeding, CCN5 knockout mice gained similar amounts of weight as their wild-type counterparts (male 2.0 vs. 1.9-fold; female 2.7 vs. 2.4-fold) but demonstrated sexual dimorphic changes in insulin sensitivity. Interestingly, male knockout mice displayed significant improvements in insulin sensitivity and glucose tolerance, despite being equally obese as their wild-type controls. The smaller improvements in female knockout mice were not as significant. At the end of the 27 weeks of HFD, the increased levels of serum insulin in response to obesity, were 30-60% lower in knockout mice (both male and female) than in wild-type counterparts, also supporting improved insulin sensitivity. Although our previous work has demonstrated that CCN5 stimulates pancreatic β-cell proliferation and survival, our assessment of the CCN5 knockout mice seems to indicate that normal, endogenous expression of CCN5/WISP2 gene is rather detrimental to metabolic compensations against diet-induced obesity, especially in male mice. These observations are not only unexpected but also contradicts to a previous report [2]. We are further characterizing potential changes in pancreatic islet morphometry and molecular markers of beta-cell function, in knockout vs. wild-type mice after HFD feeding.

Na+/H+ Exchanger 1, a Potential Therapeutic Drug Target for Cardiac Hypertrophy and Heart Failure.

Cardiac hypertrophy is defined as increased heart mass in response to increased hemodynamic requirements. Long-term cardiac hypertrophy, if not counteracted, will ultimately lead to heart failure. The incidence of heart failure is related to myocardial infarction, which could be salvaged by reperfusion and ultimately invites unfavorable myocardial ischemia-reperfusion injury. The Na+/H+ exchangers (NHEs) are membrane transporters that exchange one intracellular proton for one extracellular Na+. The first discovered NHE isoform, NHE1, is expressed almost ubiquitously in all tissues, especially in the myocardium. During myocardial ischemia-reperfusion, NHE1 catalyzes increased uptake of intracellular Na+, which in turn leads to Ca2+ overload and subsequently myocardial injury. Numerous preclinical research has shown that NHE1 is involved in cardiac hypertrophy and heart failure, but the exact molecular mechanisms remain elusive. The objective of this review is to demonstrate the potential role of NHE1 in cardiac hypertrophy and heart failure and investigate the underlying mechanisms.

Metabolic Effects of CCN5/WISP2 Gene Deficiency and Transgenic Overexpression in Mice.

CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes, and increased heart mass, but decreased fasting glucose levels. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. Not all results from these models are consistent; moreover, several important aspects of CCN5 physiology are yet to be explored.

Вплив кадмію на здоров'я дітей в пренатальний та постнатальний періоди розвитку

The purpose of the study was to analyze on the basis of foreign literature the effects of the toxic action of cadmium on the process of embryonic and postnatal development of the child, which remain insufficiently studied. The consequences of cadmium effect on children remain insufficiently studied, although cadmium is a documented developmental toxicant. The studies show that the placenta is an important target tissue for cadmium toxic effects during pregnancy. The result of the accumulation of cadmium in the placenta is as follows: a decrease in the utero-placental circulation, changes in the integrity of cells of trophoblast and cell migration, a decrease in the synthesis and metabolism of placental hormones, disorder of the placental epigenetic regulation of cell growth, as well as immune and inflammatory signal transmission. The high level of cadmium in the placenta and umbilical cord blood can be a risk factor for deterioration of infants’ state and impact on the development of a child in the future. So far, only some aspects of the toxicokinetics of the placental cadmium and its adverse effect on intrauterine growth and development are known. The level of cadmium in the mother's serum during pregnancy is associated with the risk of premature birth. There are increasing evidence on connection between the effect of cadmium and unfavorable consequences of childbirth, as well as disorders of anthropometric indicators that differ in children of different gender. In the fetus of the female gender body weight at birth tends to decrease, the chest circumference had a tendency to decrease and these indicators corresponded to an increase in the level of cadmium in the mother’s blood. Cadmium acts as an immunotoxic agent from the very early age, even very low levels of cadmium exposure during pregnancy can lead to long-term detrimental consequences for the immune system of offspring and these effects, as well as others depend on the gender. Models to study the effect of cadmium at an early age on the development of diseases in more mature age are developed. The models in mice show that the effect of cadmium on the body leads to an increase in heart mass at birth and programs hypertension development in females in adulthood. Poisoning, which occurs at an early age (in utero and in early childhood), may have a strong influence on the risk of obesity and metabolic syndrome throughout life. The chronic prenatal effect of cadmium is associated with the late development of IQ in children, while prenatal influence of passive smoking has an increased risk of delaying cognitive development of infants aged 6 months. Early mortality from various diseases, including cancer, cardiovascular, respiratory, renal and neurological problems, correlated with intrauterine or early post-natal impact of metal. Conclusion. Cadmium is classified as a potential neurotoxicant, it reaches the brain in the early stages of the development of the fetus and is associated with behavioral and cognitive dysfunction, including bad learning memory in children of early and late childhood. The adverse consequences of the prenatal effect of cadmium for the development of the fetus and subsequent health of children have discovered a number of non-solved problems, the gender should be considered as a risk factor, since cadmium causes specific results that are veiled in mixed on gender investigations

Diet-induced Obesity Differentially Modulates Cardiac Inflammatory Status in the C57 and FVB Mouse Strains.

Cardiovascular diseases correspond to the highest risk of sudden death worldwide, and obesity is largely related to be an increased risk factor. There is a higher prevalence of arterial hypertension in obese individuals, including the presence of cardiac hypertrophy. It is already known the role of toll-like receptors [TLR], mainly 2 and 4 in heart cells, as fundamental to the process of cardiac hypertrophy. Obesity has been studied as an activator of damage-associated molecular patterns [DAMPs], which use the TLR signaling pathway to increase the nuclear factor of inflammation, NF-kB, increasing cytokine expression in heart tissue. It's already known that FVB/N and C57BL/6 mouse strains have different behaviors in relation to metabolism, but the difference in cardiac tropism and innate immune system modulation are not clear. The present study aimed to evaluate the contribution of innate immune factors to cardiac hypertrophy induced by an experimental model of obesity comparing two mouse strains: C57BL/6 and FVB/N. Both strains were submitted to a high-fat diet containing 23% protein, 35.5% carbohydrate, and 35.9% fat for 68 days. Hearts were collected, weighed, and submitted to RT-qPCR, and the serum was analyzed by Bioplex. We observed an increase in heart mass after 68 days in both strains. This was followed by an increase of α-actin only in C57BL/6 while ANF was increased in FVB/N. Gene expression of innate immune components and inflammatory cytokines were only increased in C57BL/6, but not in FVB/N. Based on the results obtained, we verified that C57BL/6 mice had a more robust action of innate immune system then FVB/N.

Морфометричні показники міокарда щурів при дії загальної гіпотермії

Hypothermia is a situation in which the internal body temperature drops below 35 degrees Celsius. The article presents the relevance, theoretical aspects and features of the action of general hypothermia on the heart in general and cardiomyocytes in particular. The purpose of the study was to study the changes in the myocardium under the action of general hypothermia at different levels of structural organization. The object of the study were the hearts of laboratory adult rats. The study involved 20 animals. The longitudinal section shows that the right ventricle is much thinner than the left and its cavity is presented in the form of a crescent. The interventricular septum is thicker than the wall of the right ventricle and goes into its cavity. Results. To establish the shape of the heart and track the dynamic changes at the organ level, we calculated an index showing the ratio of the width of the heart to its length. In 80% of cases, the heart shape of intact rats was conical, the index averaged 55%, only 20% elliptical, the index was more than 65%. We did not observe other forms of heart in the group of intact rats. In the experimental groups, a spherical heart shape appeared. The thickness of the anterior wall of the left ventricle for 10 days from the beginning of the experiment was 3.15±0.11 mm, the side wall 3.1±0.11 mm, the posterior wall 2.45±0.04 mm, interventricular septum 2.95±0.09 mm. In the right ventricle, the thickness of the anterior wall is 1.04±0.03 mm, the posterior wall is 1.36±0.04 mm. On the 30th day from the beginning of the experiment, the thickness of the anterior wall of the left ventricle was 3.21±0.11 mm, the side wall 2.65±0.06 mm, the posterior wall 3.27±0.09 mm, the interventricular septum 3.14±0.13 mm. In the right ventricle, the thickness of the anterior wall is 1.09±0.04 mm, the posterior wall is 1.38±0.03 mm. Conclusions. The increase in heart mass, change in its shape due to changes in the middle third of the heart wall of both the left and right ventricles. The highest rates were in the middle third of the heart (zone "B"): In all layers of the myocardium there is an increase in the diameter of cardiomyocytes, a decrease in the distance between individual cardiomyocytes and their groups. The distance between adjacent cardiomyocytes in the left ventricle is: in the outer layer 1/8 of the diameter of the cardiomyocyte, between groups of cardiomyocytes 1/4 of the diameter of the cardiomyocyt

Use of water-alcohols treatment of medicinal plants under conditions modeling intoxication by lead and cadmium

The results of studying the effects of water-alcohol infusions of medicinal plants - rhizomes of thick-leafed incense (Bergenia crasslifolia L. Fritsch), dioica nettle leaves (Urtica dioca L.), burdock roots (Arctium lappa L.), and mother-and-leaf leaves - are presented. ordinary machichi (Tussilago farfara L.) on the organism of laboratory rats under conditions of short-term intoxication with heavy metals in doses of 25 mg of lead and 2.5 mg of cadmium per 1 kg of live weight. In the course of studies it was found that the effect of heavy metals on the body of laboratory animals is selective - the main “depot” of lead was bone tissue, and cadmium - the kidneys and liver. The addition of 1 ml of water-alcohol infusions from medicinal raw materials to the diet of rats as detoxicants caused a decrease in the level of lead in the animal organism to 6.32 times, cadmium to 3.46 times. The greatest detoxification ability was shown by infusions of the roots of burdock and leaves of nettle dioecious. Under the influence of elevated doses of lead and cadmium in laboratory animals there was an increase in heart mass by 40.34 % and spleen by 89.91 %, a decrease in the content of alkaline phosphatase in blood serum by 25.81 %. Water-alcohol infusions normalized the biochemical parameters of rat blood serum. Studies have shown that the infusions of rhizomes of thick-leafed frangipani, burdock roots, dioecious nettles and coltsfoot leaves with antioxidant properties can be the basis for the development of an effective herbal preparation used for the prevention and treatment of animals from intoxication with salts of heavy metals.

Cardiac Remodeling During Pregnancy With Metabolic Syndrome: Prologue of Pathological Remodeling.

The heart undergoes physiological hypertrophy during pregnancy in healthy individuals. Metabolic syndrome (MetS) is now prevalent in women of child-bearing age and might add risks of adverse cardiovascular events during pregnancy. The present study asks if cardiac remodeling during pregnancy in obese individuals with MetS is abnormal and whether this predisposes them to a higher risk for cardiovascular disorders. The idea that MetS induces pathological cardiac remodeling during pregnancy was studied in a long-term (15 weeks) Western diet-feeding animal model that recapitulated features of human MetS. Pregnant female mice with Western diet (45% kcal fat)-induced MetS were compared with pregnant and nonpregnant females fed a control diet (10% kcal fat). Pregnant mice fed a Western diet had increased heart mass and exhibited key features of pathological hypertrophy, including fibrosis and upregulation of fetal genes associated with pathological hypertrophy. Hearts from pregnant animals with WD-induced MetS had a distinct gene expression profile that could underlie their pathological remodeling. Concurrently, pregnant female mice with MetS showed more severe cardiac hypertrophy and exacerbated cardiac dysfunction when challenged with angiotensin II/phenylephrine infusion after delivery. These results suggest that preexisting MetS could disrupt physiological hypertrophy during pregnancy to produce pathological cardiac remodeling that could predispose the heart to chronic disorders.

Hypothalamic Norepinephrine Concentration and Heart Mass in Hypertensive ISIAH Rats Are Associated with a Genetic Locus on Chromosome 18.

The relationship between activation of the sympathetic nervous system and cardiac hypertrophy has long been known. However, the molecular genetic basis of this association is poorly understood. Given the known role of hypothalamic norepinephrine in the activation of the sympathetic nervous system, the aim of the work was to carry out genetic mapping using Quantitative Trait Loci (QTL) analysis and determine the loci associated both with an increase in the concentration of norepinephrine in the hypothalamus and with an increase in heart mass in Inherited Stress-Induced Arterial Hypertension (ISIAH) rats simulating the stress-sensitive form of arterial hypertension. The work describes a genetic locus on chromosome 18, in which there are genes that control the development of cardiac hypertrophy associated with an increase in the concentration of norepinephrine in the hypothalamus, i.e., genes involved in enhanced sympathetic myocardial stimulation. No association of this locus with the blood pressure was found. Taking into consideration previously obtained results, it was concluded that the contribution to the development of heart hypertrophy in the ISIAH rats is controlled by different genetic loci, one of which is associated with the concentration of norepinephrine in the hypothalamus (on chromosome 18) and the other is associated with high blood pressure (on chromosome 1). Nucleotide substitutions that may be involved in the formation or absence of association with blood pressure in different rat strains are discussed.

Cardioprotective Function of Green Rooibos (Aspalathus linearis) Extract Supplementation in Ex Vivo Ischemic Prediabetic Rat Hearts.

Diabetic patients develop ischemic heart disease and strokes more readily. Following an ischemic event, restoration of blood flow increases oxidative stress resulting in myocardial damage, termed ischemia/reperfusion injury. Aspalathus linearis (rooibos), rich in the antioxidant phenolic compound aspalathin, has been implicated as cardioprotective against ischemia/reperfusion injury with undefined mechanism in control rats. Primarily, the therapeutic potential of Afriplex green rooibos extract to prevent ischemia/reperfusion injury in cardiovascular disease-compromised rats was investigated. Additionally, Afriplex Green rooibos extract's cardioprotective signaling on metabolic markers and stress markers was determined using western blotting. Three hundred male Wistar rats received either 16-wk standard diet or high-caloric diet. During the final 6 wk, half received 60 mg/kg/day Afriplex green rooibos extract, containing 12.48% aspalathin. High-caloric diet increased body weight, body fat, fasting serum triglycerides, and homeostatic model assessment of insulin resistance - indicative of prediabetes. High-caloric diet rats had increased heart mass, infarct size, and decreased heart function. Afriplex green rooibos extract treatment for 6 wk lowered pre-ischemic heart rate, reduced infarct size, and improved heart function pre- and post-ischemia, without significantly affecting biometric parameters. Stabilized high-caloric diet hearts had decreased insulin independence via adenosine monophosphate activated kinase and increased inflammation (p38 mitogen-activated protein kinase), whereas Afriplex green rooibos extract treatment decreased insulin dependence (protein kinase B) and conferred anti-inflammatory effect. After 20 min ischemia, high-caloric diet hearts had upregulated ataxia-telangiectasia mutated kinase decreased insulin independence, and downregulated insulin dependence and glycogen synthase kinase 3 β inhibition. In contrast, Afriplex green rooibos extract supplementation downregulated insulin independence and inhibited extracellular signal-regulated kinase 1 and 2. During reperfusion, all protective signaling was decreased in high-caloric diet, while Afriplex green rooibos extract supplementation reduced oxidative stress (c-Jun N-terminal kinases 1 and 2) and inflammation. Taken together, Afriplex green rooibos extract supplementation for 6 wk preconditioned cardiovascular disease-compromised rat hearts against ischemia/reperfusion injury by lowering inflammation, oxidative stress, and heart rate.

Marker profile of myocardial remodeling in different etiopathogenetic forms of arterial hypertension in the experiment

The aim was to determine the morphodensitometric parameters of cardiomyocytes and features of the marker profile of remodeling in the left ventricular myocardium of rats with experimental hypertension of different etiopathogenetic forms.Materials and methods. The experiment was conducted on 20 male Wistar rats and 10 SHR which were divided into two groups of 10 animals each: the 1st –control; the 2nd – rats of the SHR line (EAH); the 3rd – 10 male Wistar rats with endocrine-salt arterial hypertension. Systolic and diastolic BP levels were measured in all the rats using the system of non-invasive arterial pressure measurement BP-2000. The objects of the study were myocardial sections in which the content of immunoreactive material to remodeling markers (cardiotrophin-1, titin, collagen type I, annexin V) was determined by the immunofluorescent method, titin / collagen ratio was calculated, the average linear size of cardiomyocyte nuclei, their density, RNA concentrations in the nucleus and cytoplasm were determined by morphodensitometric method.Results. Arterial hypertension, regardless of its etiopathogenetic form, is characterized by an increase in the number of cardiomyocyte nuclei with an increase in their size, decrease in the density and decrease in their RNA concentration against increase in the cytoplasm. In rats with EAH, the content of cardiotrophin-1 was higher than the control by 27 %, and in ESAH by 80 %. Titin levels were 12% higher in EAH and 46 % in ESAH. The collagen type I content of EAH was higher than the control by 49 %, while in the group with ESAH by 68 %. EAH rats had a higher annexin V content by 58 %, while ESAH – 64 %. The ratio of the content of titin and type I collagen in control rats was 1.01, in rats with EAH decreased to 0.76, while in rats ESAH it was 1.3.Conclusions. The formation of arterial hypertension, regardless of its etiopathogenetic form, leads to the development of pathological myocardial remodeling, as indicated by increased heart mass and specific gravity, changes in the cytoarchitectonics of cardiomyocytes, the development of polymorphism of their nuclei with increasing size against increasing of its number with nuclear dysfunction. The marker profile of myocardial remodeling in rats with essential hypertension is characterized by a moderate increase in cardiotrophin-1 and titin, with a significant increase in collagen type I and annexin V, which in combination with a low ratio of titin / collagen type indicates fibrosis with increased myocardial stiffness and the development of hypertrophic-fibrous type of myocardial remodeling with moderate apoptosis. In rats with endocrine-salt arterial hypertension, the marker profile of myocardial remodeling is characterized by a significant increase in all 4 immunohistochemical markers of remodeling, moderate fibrosis and an increase in the titin / collagen ratio, which is characteristic of hypertrophic-apoptotic type of pathological remodeling.

Glycolaldehyde-Derived High-Molecular-Weight Advanced Glycation End-Products Induce Cardiac Dysfunction through Structural and Functional Remodeling of Cardiomyocytes.

High-molecular-weight advanced glycation end-products (HMW-AGEs) are abundantly present in our Western diet. There is growing evidence reporting that HMW-AGEs contribute to the development of cardiovascular dysfunction in vivo, next to the well-known low-molecular-weight AGEs. The goal of our study is to assess the ultrastructure and function of cardiomyocytes after chronic exposure to HMW-AGEs. A better understanding of underlying mechanisms is essential to create new opportunities for further research on the specific role of HMW-AGEs in the development and progression of cardiovascular diseases. Adult male rats were randomly assigned to daily intraperitoneal injection for six weeks with either HMW-AGEs (20 mg/kg/day) or a control solution. Hemodynamic measurements were performed at sacrifice. Single cardiomyocytes from the left ventricle were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Unloaded cell shortening, time to peak and time to 50% relaxation were measured during field stimulation and normalized to diastolic length. L-type Ca2+ current density (ICaL) and steady-state inactivation of ICaL were measured during whole-cell ruptured patch clamp. Myofilament functional properties were measured in membrane-permeabilized cardiomyocytes. Ultrastructural examination of cardiac tissue was performed using electron microscopy. Rats injected with HMW-AGEs displayed in vivo cardiac dysfunction, characterized by significant changes in left ventricular peak rate pressure rise and decline accompanied with an increased heart mass. Single cardiomyocytes isolated from the left ventricle revealed concentric hypertrophy, indicated by the increase in cellular width. Unloaded fractional cell shortening was significantly reduced in cells derived from the HMW-AGEs group and was associated with slower kinetics. Peak L-type Ca2+ current density was significantly decreased in the HMW-AGEs group. L-type Ca2+ channel availability was significantly shifted towards more negative potentials after HMW-AGEs injection. The impact of HMW-AGEs on myofilament function was measured in membrane-permeabilized cardiomyocytes showing a reduction in passive force, maximal Ca2+ activated force and rate of force development. Ultrastructural examination of cardiac tissue demonstrated adverse structural remodeling in HMW-AGEs group characterized by a disruption of the cyto-architecture, a decreased mitochondrial density and altered mitochondrial function. Our data indicate that HMW-AGEs induce structural and functional cellular remodeling via a different working mechanism as the well-known LMW-AGEs. Results of our research open the door for new strategies targeting HMW-AGEs to improve cardiac outcome.

Wnt-C59 Attenuates Pressure Overload-Induced Cardiac Hypertrophy via Interruption of Wnt Pathway.

BackgroundCardiac hypertrophy usually results in heart failure and is an important cause of mortality worldwide. Wnt/β-catenin signaling pathway hyper-activation is involved in the pathogenesis and progression of cardiac hypertrophy. Wnt-C59 is a small molecular compound, which strongly and specifically targets at Porcupine to pharmacologically inhibit Wnt palmitoylation, secretion, and other biological activities. However, the role of Wnt-C59 in cardiac hypertrophy remains unknown.Material/MethodsWe performed transverse aortic constriction (TAC) in adult male mice to induce pressure overload and establish an in vivo model of cardiac hypertrophy. Angiotensin II (Ang-II) was utilized to culture cardiomyocyte to establish a model of in vitro cardiomyocyte hypertrophy. Daily administration of Porcupine inhibitor Wnt-C59 was performed for 4 weeks after TAC surgery.ResultsWnt-C59 significantly improved cardiac function and enhanced survival of mice subjected to TAC surgery. Histologically, Wnt-C59 attenuated TAC-induced increase in heart mass, cross-section area of cardiomyocyte, cardiac fibrosis, cardiomyocyte apoptosis, and expression of the hypertrophic biomarkers β-MHC, ANP, and BNP. TAC-induced oxidative stress was also ameliorated by Wnt-C59. Wnt-C59 attenuated Ang-II-induced in vitro cardiomyocyte hypertrophy, as indicated by decreased cell size and lower expression of ANP, BNP, and β-MHC. Moreover, Wnt/β-catenin activation was blocked by Wnt-C59 in cardiac hypertrophy, as indicated by decreased protein expression of Wnt3a and β-catenin and the Wnt target genes cyclin D1 and c-Myc.ConclusionsCollectively, Porcupine inhibitor Wnt-C59 attenuates pressure overload-induced cardiac hypertrophic via interruption of the Wnt/β-catenin signaling pathway, and it might be a promising drug for patients with cardiac hypertrophy.