Development Of Myocardial Hypertrophy Research Articles

Effect of fibroblasts small- conductance Ca2+ -activated potassium channel subtype 2 (SK2) on myocardial fibrosis in pressure overload mouse

Studies have shown that Small conductance Ca2 + −activated K+ (SK) channel are expressed in fibroblasts. We aimed to determine the expression of SK2 channels in cardiac fibroblasts during myocardial hypertrophy and investigate its relationship with fibrotic remodeling. Myocardial hypertrophy and fibrotic remodeling induced by transverse aortic constriction (TAC) were assessed by echocardiography, Masson's trichrome staining and Western blot. Knockdown and overexpression of the SK2 protein were used to assess relationship between SK2 expression in fibroblasts and myocardial fibrosis. There is a positive correlation between myocardial fibrosis and SK2 channel protein expression during the development of myocardial hypertrophy. The differentiation and secretion of fibroblasts in mice with cardiac hypertrophy are enhanced, and the expression of SK2 channel protein is increased. Manipulating SK2 levels in fibroblasts can either promote or inhibit their differentiation and secretory function. Knocking down SK2 reduces the up-regulation of TGF β1, p-Smad2/3/GAPDH, p-p38/GAPDH, p-ERK1/2/GAPDH, and p-JNK/GAPDH proteins induced by Ang II in cardiac fibroblasts without significantly affecting total protein levels. AAV9-SK2-RNAi injection in mice improves cardiac function. Collectively, our study suggests that the expression of the SK2 channel is significantly increased in fibroblasts of mice with myocardial hypertrophy, potentially impacting myocardial fibrosis remodeling via the TGF-β signaling pathway.

Reduced DNMT1 levels induce cell apoptosis via upregulation of METTL3 in cardiac hypertrophy

DNA methylation is also involved in the development and progression of cardiac diseases. Although studies have shown that DNA methylation and RNA m6A methylation play an important role in the development of myocardial hypertrophy, whether DNA methylation and RNA m6A methylation have a coordinated role in the development of myocardial hypertrophy and influence each other is still unknown. Here, we found that DNMT1 expression was downregulated in TAC mice and Ang II-treated NRCMs. Moreover, DNMT1 overexpression inhibited Ang II-induced apoptosis of NRCMs. Furthermore, we found that the expression of METTL3 was up-regulated after inhibiting the expression of DNMT1 by a DNMT1 inhibitor or small interfering RNA. In addition, ectopic expression DNMT1 inhibited METTL3 expression in NRCMs. Furthermore, METTL3 expression was elevated in NRCMs treated with Ang II, and suppression of METTL3 inhibited cell apoptosis induced by Ang II in NRCMs.In addition, this study revealed that the DNMT1/METTL3 pathway affected Ang II-induced apoptosis in NRCMs. Finally, this study found that DNMT1, but not METTL3, might directly regulated the ANP and BNP expression. Collectively, our findings revealed the role of the DNMT1/METTL3 pathway in cardiac hypertrophy and provided a novel molecular mechanism describing the physiological and pathological processes.

Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation.

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

TBC1D25 alleviates nonalcoholic steatohepatitis by inhibiting abnormal lipid accumulation and inflammation.

Nonalcoholic fatty liver disease (NAFLD) is a strong stimulant of cardiovascular diseases, affecting one-quarter of the world's population. TBC1 domain family member 25 (TBC1D25) regulates the development of myocardial hypertrophy and cerebral ischemia-reperfusion injury; however, its effect on NAFLD/nonalcoholic steatohepatitis (NASH) has not been reported. In this study, we demonstrated that TBC1D25 expression is upregulated in NASH. TBC1D25 deficiency aggravated hepatic steatosis, inflammation, and fibrosis in NASH. In vitro tests revealed that TBC1D25 overexpression restrained NASH responses. Subsequent mechanistic validation experiments demonstrated that TBC1D25 interfered with NASH progression by inhibiting abnormal lipid accumulation and inflammation. TBC1D25 deficiency significantly promoted NASH occurrence and development. Therefore, TBC1D25 may potentially be used as a clinical therapeutic target for NASH treatment.

Morphofunctional features of the myocardium in patients with severe obstructive sleep apnea syndrome and their dynamics during continuous positive airway pressure therapy

This paper presents the echocardiographic morphofunctional parameters of the myocardium of patients suffering from severe obstructive sleep apnea syndrome and their dynamics before and after treatment with the help of the SYNAP apparatus by creating a constant positive pressure on inspiration during sleep. All patients were divided into two groups: the experimental group suffering from severe obstructive sleep apnea syndrome and the control group without cardiovascular and respiratory diseases. After echocardiography, the experimental group underwent a course of continuous constant positive pressure on inspiration during sleep. The symptoms of severe obstructive sleep apnea syndrome were determined by the presence of daytime drowsiness, loud snoring, witnessed breathing interruptions, or awakenings due to shortness of breath or suffocation, in the presence of at least 30 obstructive respiratory complications (apnea, hypopnea, or excitement associated with respiratory effort) in 1 h of sleep. In the experimental group, remodeling of heart chambers was observed, manifested mainly by an increase in the volume of the left atrium, dilatation of the right ventricle, and development of myocardial hypertrophy of the left and right ventricles. The systolic function of the right ventricle and the diastolic dysfunction of the right and left ventricles decreased, and the systolic pressure in the pulmonary artery increased. A course of continuous constant positive inhalation pressure during sleep in the experimental group led to reverse remodeling of the heart chambers and improvement of the systolic function of the myocardium of both ventricles. A 3-month course of continuous constant positive pressure on inspiration during sleep led to a persistent decrease in systolic pressure in the pulmonary artery. The constant application of continuous, constant positive pressure on inhalation during sleep can prevent the progression of systolic and diastolic abnormalities and reverse these changes in the initial stages before serious structural changes can develop.

Analysis of Therapeutic Targets of A Novel Peptide Athycaltide-1 in the Treatment of Isoproterenol-Induced Pathological Myocardial Hypertrophy

Myocardial hypertrophy is a pathological feature of many heart diseases. This is a complex process involving all types of cells in the heart and interactions with circulating cells. This study is aimed at identifying the differentially expressed proteins (DEPs) in myocardial hypertrophy rats induced by isoprenaline (ISO) and treated with novel peptide Athycaltide-1 (ATH-1) and exploring the mechanism of its improvement. ITRAQ was performed to compare the three different heart states in control group, ISO group, and ATH-1 group. Pairwise comparison showed that there were 121 DEPs in ISO/control (96 upregulated and 25 downregulated), 47 DEPs in ATH-1/ISO (27 upregulated and 20 downregulated), and 116 DEPs in ATH-1/control (77 upregulated and 39 downregulated). Protein network analysis was then performed using the STRING software. Functional analysis revealed that Hspa1 protein, oxidative stress, and MAPK signaling pathway were significantly involved in the occurrence and development of myocardial hypertrophy, which was further validated by vivo model. It is proved that ATH-1 can reduce the expression of Hspa1 protein and the level of oxidative stress in hypertrophic myocardium and further inhibit the phosphorylation of p38 MAPK, JNK, and ERK1/2.

RIP3 Contributes to Cardiac Hypertrophy by Influencing MLKL-Mediated Calcium Influx.

Receptor-interacting protein 3(RIP3), a RIP family member, has been reported as a critical regulator of necroptosis and involves in the pathogenesis of various heart diseases. However, its role in the development of myocardial hypertrophy after pressure overload is unclear. We aimed to investigate the roles of RIP3 in pathological cardiac hypertrophy. A rat model of myocardial hypertrophy induced by the aortic banding method was used in this study. Neonatal rat cardiomyocytes (NRCMs) were stimulated with angiotensin II (Ang-II) or phenylephrine (PE) to induce neurohumoral stress. Our results showed that RIP3 level was significantly elevated in the hypertrophic myocardium tissues from patients, rats subjected to AB surgery, and NRCMs treated with Ang-II or PE. After downregulation of RIP3 expression in NRCMs, the phenotypes of myocardial hypertrophy were obviously alleviated. In mechanism, we demonstrated that RIP3 interacts with mixed lineage kinase domain-like protein (MLKL) and promotes its cell membrane localization to increase the influx of calcium within cells, thereby mediating the development of myocardial hypertrophy. More interestingly, we found the blockage of calcium influx by 2-aminoethoxydiphenyl borate, and lanthanum chloride efficiently reverses RIP3-induced cardiac remodeling in NRCMs. Taken together, our findings indicate a key role of the RIP3-MLKL signaling pathway in myocardial hypertrophy, which may be a novel promising treatment strategy for myocardial hypertrophy.

Understanding the Genetic and Molecular Basis of Familial Hypertrophic Cardiomyopathy and the Current Trends in Gene Therapy for Its Management.

Hypertrophic cardiomyopathy (HCM) is a genetically acquired disease of cardiac myocytes. Studies show that 70% of this disease is a result of different mutations in various sarcomere genes. This review aims to discuss several genetic mutations, epigenetic factors, and signal transduction pathways leading to the development of HCM. In addition, this article elaborates on recent advances in gene therapies and their implications for managing this condition. We start by discussing the founding mutations in HCM and their effect on power stroke generation. The less explored field of epigenetics including methylation, acetylation, and the role of different micro RNAs in the development of cardiac muscle hypertrophy has been highlighted in this article. The signal transduction pathways that lead to gene transcription, which in turn lead to increased protein synthesis of cardiac muscle fibers are elaborated. Finally, the microscopic events leading to the pathophysiologic macro events of cardiac failure, and the current experimental trials of gene therapy models, and the clustered regularly interspaced short palindromic repeats (CRISPR) type 2 system proteins, are discussed. We have concluded our discussion by emphasizing the need for more studies on epigenomics and experimental designs for gene therapy in HCM patients. This review focuses on the process of HCM from initial mutation to the development of phenotypic expression and various points of intervention in cardiac myocardial hypertrophy development.

Cholecystokinin Expression in the Development of Myocardial Hypertrophy.

Background Expression of cholecystokinin is found in myocardial tissues as a gastrointestinal hormone and may be involved in cardiovascular regulation. However, it is unclear whether there is an increase in cholecystokinin expression in myocardial hypertrophy progression induced by abdominal aortic constriction. The study is aimed at exploring the relationship between cholecystokinin expression and myocardial hypertrophy. Methods We randomly divided the 70 Sprague-Dawley rats into two groups: the sham operation group and the abdominal aortic constriction group. The hearts of rats were measured by echocardiography, and myocardial tissues and blood were collected at 4 weeks, 8 weeks, and 12 weeks after surgery. Morphological changes were assessed by microscopy. The cholecystokinin expression was evaluated by immunochemistry, Western blotting, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Results The relative protein levels of cholecystokinin were significantly increased in the abdominal aortic constriction groups compared with the corresponding sham operation groups at 8 weeks and 12 weeks. The cholecystokinin mRNA in the abdominal aortic constriction groups was significantly higher than the time-matched sham operation groups. Changes in the left ventricular wall thickness were positively correlated with the relative protein levels of cholecystokinin and the mRNA of cholecystokinin. Conclusions The development of myocardial hypertrophy can affect the cholecystokinin expression of myocardial tissues.

CHANGES IN CARDIOVASCULAR AND RESPIRATORY SYSTEMS IN YOUNG ATHLETES

Changes in cardiorespiratory complex of adult athletes are the subject of scientific researches. However, there is a lack of researches that would assess such changes in children and adolescents involved in intensive physical training. The purpose of the study was to evaluate functional and morphological changes of cardiovascular and respiratory systems in boys of primary school age engaged in football. Materials and methods. 109 male children aged 10-11 years were enrolled in the study, among which 81 children have been attending sports football schools, 28 children didn’t have regular physical activity. The study design included a general clinical examination, a spirometry, the condition of cardiovascular system was assessed with echocardiography, and ambulatory blood pressure monitoring (ABPM). Results. The boys 10-11 years of age who play sports have higher values of minute respiratory volume and cardiac indices, which may support the hypothesis of the myocardial hypertrophy development, although they correspond to normal Z-score values. According to ABPM results the duration of physical activity may influence on transition from vasodilation to vasoconstriction. Conclusions. We obtained statistically significant quantitative differences in the functional state of the cardiovascular and respiratory systems in children-athletes. The changes found in young athletes may result to further supervision of a pediatric cardiologist, but decision should be made individually.

AORTIC STENOSIS, DIAGNOSIS, TREATMENT TACTICS. WHAT IS IMPORTANT FOR THE THERAPIST TO KNOW?

Aortic stenosis is the most common manifestation of valve heart disease, which requires surgical or endovascular intervention. The prevalence of degenerative aortic stenosis is increasing due to an aging population. The clinical course of aortic stenosis is characterized by a long-existing asymptomatic period. The progressive calcification of the valve cusps leads to the formation of a pressure gradient in the aorta, hemodynamic overload of the left ventricle, the development of myocardial hypertrophy, which contributes to the violation of diastolic function of the left ventricle. After the onset of symptoms of aortic stenosis, the two-year survival in patients who do not undergo surgical correction does not exceed 50 %. The Recommendations of the European Association of Cardiology and the European Association of Cardiothoracic Surgeons for the treatment of patients with valvular heart disease in 2017 discuss aspects of the diagnosis of aortic stenosis and the principles of choosing tactics for managing patients using surgical or catheter treatment methods. Depending on the severity of aortic stenosis, its clinical manifestations, age of patients, and associated pathology, surgical replacement of the aortic valve or its transcatheter implantation may be recommended. The use of drug therapy for aortic stenosis did not show the possibility of improving the prognosis. Drug therapy is used to treat heart failure, hypertension. Important tasks are the control of sinus rhythm and the prevention of thromboembolic complications.

Identification of Single-Nucleotide Polymorphisms in Mitochondria-Associated Genes Capable of Affecting the Development of Hypertrophic Cardiomyopathy in Senescence-Accelerated OXYS Rats

Hypertrophic cardiomyopathy (HC) is a heterogeneous myocardial disease with a wide range of clinical manifestations, and the risk of its development increases with age against the background of myocardial changes that are characteristic of aging. The contribution of the genetic component to the development of HC is obvious; however, the etiology and pathogenesis of this disease remain unclear in 50% of cases. The goal of the study was to search for single-nucleotide polymorphisms in mitochondria-associated genes, which can contribute to the development of myocardial hypertrophy in senescence-accelerated OXYS rats, based on the results of RNA-Seq. Polymorphisms with a potential negative effect on the function of the protein product in the mitochondria-associated genes Fbxl4 and Slc25a32, mutations in which were not previously associated with HC, were revealed. Changes in the expression of these genes in the myocardium of OXYS rats at different stages of the development of pathological changes indicate that the identified polymorphisms can contribute to the development of HC. Thus, polymorphisms in the genes Fbxl4 and Slc25a32, as well as the genes themselves, can be considered promising molecular targets in the study of the contribution of mitochondrial dysfunction to the development of myocardial hypertrophy.

Changes in the expression of the MADD gene in experimental models of myocardial hypertrophy

Objective. The aim of the work was to evaluate the expression of the MADD gene during the development of myocardial hypertrophy caused by hemodynamic factors in the model of aortic coarctation, as well as in the model of renovascular arterial hypertension (model “2 kidney — 1 clip”). Design and methods. The study involved Wistar rats (n = 60) at the age of 8 weeks. Two experimental models of myocardial hypertrophy were used: the aortic coarctation model (n = 30) and the “2 kidneys — 1 clip” model (n = 21). Animals were divided into groups according to the duration of the experiment (1 and 10 weeks), we also formed a group of intact animals (n = 9). Myocardial hypertrophy was verified by echocardiography. After euthanasia and myocardial extraction, the tissues were homogenized in Extract RNA reagent (Evrogen) in order to obtain RNA. A complementary DNA strand was obtained by reverse transcription using Random (dN) 10-primer (Evrogen) and MMLV RT kit (Evrogen) primers. The relative expression level of the MADD gene in rat myocardium was determined using real-time polymerase chain reaction. The expression level was calculated using the ΔΔCt method; the GAPDH and HPRT genes were used as a reference control. Results. In the aortic coarctation model, MADD gene expression in the 1-week group was significantly higher (p < 0,05) compared with the intact group. In this model, there as a direct correlation of the expression of the MADD gene with NPPA gene, as well as with echocardiography indicators (final systolic size, final diastolic size, and myocardial mass index, p < 0,05), and an inverse relationship between MADD gene expression and the shortening fraction (p < 0,05). The renovascular hypertension model did not show a significant increase in the expression of the MADD gene in myocardium in experimental group compared to intact animals. Conclusions. The expression of the MADD gene increases mainly under the influence of acute hemodynamic overload, and is likely to be important for the immediate response by cardiomyocytes to pressure load. Correlation was found between the expression level of the MADD gene and such echocardiographic parameters as the shortening fraction, end-diastolic and end-systolic sizes of the left ventricle.

LncRNA-Mhrt regulates cardiac hypertrophy by modulating the miR-145a-5p/KLF4/myocardin axis

Cardiac hypertrophy is an early milestone of many heart diseases. LncRNAs often play a leading role in this process. However, its mechanism of action in cardiac hypertrophy has not been fully explained. In a previous study, we showed a new mode by which lncRNA-Mhrt inhibited cardiac hypertrophy by inhibiting myocardin. However, the underlying molecular mechanism remains unclear. This study aims to explore potential action modes of Mhrt in regulating the expression of myocardin in the process of cardiac hypertrophy. Here, we find that Mhrt reduces myocardin expression through KLF4 in vivo and in vitro. Meanwhile, Mhrt promotes the expression of KLF4 through direct binding to miR-145a-5p or inhibiting phosphorylation of KLF4 by forming a complex with KLF4 to prevent the binding of ERK and KLF4, thereby inhibiting myocardin expression and the development of myocardial hypertrophy. Taken together, our findings reveal a new pathway, Mhrt-KLF4-myocardin, that regulates cardiac hypertrophy and revealed additional possible action modes of Mhrt in the occurrence and development of cardiac hypertrophy. The new regulatory pathway serves as a potential therapeutic avenue for cardiac hypertrophy.

SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)-Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation.

S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload. Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography-tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA-transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model. SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography-tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy. Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.

The CaMKII phosphorylation site Thr1604 in the CaV1.2 channel is involved in pathological myocardial hypertrophy in rats

ABSTRACT Residue Thr1604 in the CaV1.2 channel is a Ca2+/calmodulin dependent protein kinase II (CaMKII) phosphorylation site, and its phosphorylation status maintains the basic activity of the channel. However, the role of CaV1.2 phosphorylation at Thr1604 in myocardial hypertrophy is incompletely understood. Isoproterenol (ISO) was used to induce cardiomyocyte hypertrophy, and autocamtide-2-related inhibitory peptide (AIP) was added as a treatment. Rats in a myocardial hypertrophy development model were subcutaneously injected with ISO for two or three weeks. The heart and left ventricle weights, each of which were normalized to the body weight and cross-sectional area of the myocardial cells, were used to describe the degree of hypertrophy. Protein expression levels were detected by western blotting. CaMKII-induced CaV1.2 (Thr1604) phosphorylation (p-CaV1.2) was assayed by coimmunoprecipitation. The results showed that CaMKII, HDAC, MEF2 C, and atrial natriuretic peptide (ANP) expression was increased in the ISO group and downregulated by AIP treatment in vitro. There was no difference in the expression of these proteins between the ISO 2-week group and the ISO 3-week group in vivo. CaV1.2 channel expression did not change, but p-CaV1.2 expression was increased after ISO stimulation and decreased by AIP. In the rat model, p-CaV1.2 levels and CaMKII activity were much higher in the ISO 3-week group than in the ISO 2-week group. CaMKII-induced CaV1.2 channel phosphorylation at residue Thr1604 may be one of the key features of myocardial hypertrophy and disease development.Abbreviations: CaMKII: Ca2+/calmodulin dependent protein kinase II; p-CaMKII: autophosphorylated Ca2+/calmodulin dependent protein kinase II; CaM: calmodulin; AIP: autocamtide-2-related inhibitory peptide; ECC: excitation-contraction coupling; ISO: isoproterenol; BW: body weight; HW: heart weight; LVW: left ventricle weight; HDAC: histone deacetylase; p-HDAC: phosphorylated histone deacetylase; MEF2C: myocyte-specific enhancer factor 2C; ANP: atrial natriuretic peptide; PKC: protein kinase C

THE IGF -I IN DIABETIC PATIENTS WITH RESISTANT HYPERTENSION DECREASES INSULIN RESISTANCE BUT IS ASSOCIATED WITH CARDIOVASCULAR TARGET ORGAN DAMAGE

Objective: The insulin-like growth factor-I (IGF-I) is involved in glucose metabolism and may contribute to the accelerated cardiovascular disease. The aim of the study was to assess IGF-I level in diabetic patients with resistant hypertension (RHTN) and to evaluate its association with glucose metabolism and cardiac, renal and brain tissues. Design and method: The study included 19 diabetic patients with RHTN (mean age 58.9 ± 7.6 years, five men, mean office BP (systolic/diastolic) 174.8 ± 20.7/94.6 ± 15mmHg, mean HbA1c 7 ± 0.8%) and 21 age- and sex-matched patients with RHTN without diabetes mellitus (DM). Office BP, echocardiography, kidney and brain MRI, lab tests (IGF-1, plasma glucose and insulin levels, HOMA-index, HbA1c, serum creatinine, serum cystatin, eGFR (MDRD formula) and 24 h microalbuminuria) were performed in all patients. On average, patients were taking 4.2 ± 0.8 antihypertensive drugs. Results: IGF-I level was in the normal range in 18 (95%) patients with DM+RHTN and in 100% of patients with RHTN without DM, one diabetic patient with RHTN had elevated IGF-I levels. The mean IGF-I values in hypertensive patients with DM and those without DM were the same. In diabetic patients with RHTN the IGF-I level was inversely correlated to HOMA-IR index (R = -0.87, P = 0.002), but had a direct correlation with basal glucose level (R = 0.48, P = 0.04). In addition, increase in IGF-I level was associated with both of left ventricular mass (R = 0.49, P = 0.03), and the end-diastolic interventricular septum thickness (R = 0.59, P = 0.008), with decreased renal function (R = 0.64, P = 0.003 for serum creatinine; R = 0.76, p = 0.01 for serum cystatin; R = -0.50, P = 0.03 for eGFR), microalbuminuria level (R = 0.61, P = 0.03), as well as with structural kidney damage (R = -0.67, P = 0.04 for the medulla volume according to kidney MRI) and brain damage (R = 0.89, P = 0.015 for Evans’ index as a MRI- sign of brain atrophy) Conclusions: Most diabetic patients with RHTN have a normal IGF-I level, which does not differ from that in patients with RHT without DM. Although an increase in IGF-I level is associated with a decrease in insulin resistance, our data suggest the possible participation of IGF-I in the development of myocardial hypertrophy, the progression both of chronic kidney disease and brain atrophy.

Molecular biomarkers in cardiac hypertrophy.

Cardiac hypertrophy is characterized by an increase in myocyte size in the absence of cell division. This condition is thought to be an adaptive response to cardiac wall stress resulting from the enhanced cardiac afterload. The pathogenesis of heart dysfunction, which is one of the primary causes of morbidity and mortality in elderly people, is often associated with myocardial remodelling caused by cardiac hypertrophy. In order to well understand the potential mechanisms, we described the molecules involved in the development and progression of myocardial hypertrophy. Increasing evidence has indicated that micro‐RNAs are involved in the pathogenesis of cardiac hypertrophy. In addition, molecular biomarkers including vascular endothelial growth factor B, NAD‐dependent deacetylase sirtuin‐3, growth/differentiation factor 15 and glycoprotein 130, also play important roles in the development of myocardial hypertrophy. Knowing the regulatory mechanisms of these biomarkers in the heart may help identify new molecular targets for the treatment of cardiac hypertrophy.

CLINICAL VALUE OF BLOOD BIOMARKERS IN PATIENTS WITH CHRONIC HEART FAILURE

Biomarkers (various laboratory biochemical markers), such as natriuretic peptides (NP), soluble ST2 receptor, copeptin, galectin-3, are widely studied in patients with chronic heart failure (CHF). The European Society of Cardiology recommends the determination of blood NP level in suspicion of HF and its use as one of the mandatory diagnostic criteria for CHF with preserved and mid-range ejection fraction. Dynamics of NP concentration may be predictor of the effectiveness of the therapy and the necessity of the titration of the dose of HF drugs. Neprilyzin destroys NP, but does not destroy their precursors, including NT-proBNP. Therefore, it is necessary to use NT-proBNP as a marker of therapeutic efficacy and prognosis when using neprilysine inhibitors (sacubitril). ST2 is a protein receptor for interleukin-33 (IL-33). The transmembrane ST2 (ST2L) binds to IL-33 and forms the IL-33/ST2L complex, which has a cardioprotective effect, prevents the development of myocardial hypertrophy, fibrosis and apoptosis. The soluble ST2 receptor (sST2) is a “trap” for IL-33 and neutralizes the protective effects of the IL-33/ST2L complex, which leads to hypertrophy and fibrosis of the myocardium, dilatation of the chambers and reduction of the contractility of the heart. It can be considered as a marker of unfavorable prognosis in heart failure, but it is not specific. Copeptin is a part of the arginine-vasopressin, or antidiuretic hormone, precursor which plays an important role in the pathogenesis of CHF. Since arginine-vasopressin has a short half-life and is unstable outside the body, copeptin is being actively investigated. Its level increases during the CHF decompensation and relates with the functional class of CHF. A combined measurement of the concentration of copeptin and NP may improve the risk stratification in CHF patients. Galectin-3 is a peptide that stimulates the activation of fibroblasts and the development of fibrosis. It increases in CHF patients and is associated with the severity of the condition, systolic and diastolic LV dysfunction and prognosis. Currently, NP are the best biomarkers that can and should be used in routine clinical practice. To prove the need for widespread use of other biomarkers, additional research is needed.

Inhibition of microRNA-143-3p attenuates myocardial hypertrophy by inhibiting inflammatory response.

MicroRNA-143-3p (miR-143-3p) is involved in the initiation of inflammatory response and the progression of cardiovascular diseases. Myocardial hypertrophy is a common symptom in numerous cardiovascular diseases. In the current study, we attempted to demonstrate the role of miR-143-3p in the development of myocardial hypertrophy by focusing on its association with inflammation. Myocardial hypertrophy was induced by transverse aortic constriction (TAC) method in vivo and by H2 O2 administration in vitro. The expression status of miR-143-3p and downstream effectors were detected in animal heart tissues and H9c2 cells. Furthermore, the effect of miR-143-3p inhibition on H2 O2 -induced changes in ERK5/PPARδ/NF-κB axis was assessed. TAC induced oxidative stress and inflammation in rat heart tissues, which was associated with the increased expressions of miR-143-3p and p-ERK5. However, the up-regulated expression of miR-143-3p had no effect on the expression of ERK5, which was a direct target of miR-143-3p. The results of in vitro assays showed that H2 O2 administration increased the levels of miR-143-3p and p-EKR5 and induced the activation of NF-κB pathway. After the inhibition of miR-143-3p, the activation of EKR5 and NF-κB pathway was suppressed, whereas the expression of PPARδ was up-regulated. The current study demonstrated that miR-143-3p is crucial to the initiation of inflammatory response induced by myocardial hypertrophy. The activation of ERK5 following miR-143-3p up-regulation appears to be a complementary response to induce the subsequent anti-inflammatory signaling transduction, which needed further exploration.