Antihypertrophic Memory After Regression of Exercise-Induced Physiological Myocardial Hypertrophy Is Mediated by the Long Noncoding RNA Mhrt779.

BACKGROUND: Exercise can induce physiological myocardial hypertrophy (PMH), and former athletes can live 5 to 6 years longer than nonathletic controls, suggesting a benefit after regression of PMH. We previously reported that regression of pathological myocardial hypertrophy has antihypertrophic effects. Accordingly, we hypothesized that antihypertrophic memory exists even after PMH has regressed, increasing myocardial resistance to subsequent pathological hypertrophic stress. METHODS: C57BL/6 mice were submitted to 21 days of swimming training to develop PMH. After termination of exercise, PMH regressed within 1 week. PMH regression mice (exercise hypertrophic preconditioning [EHP] group) and sedentary mice (control group) then underwent transverse aortic constriction or a sham operation for 4 weeks. Cardiac remodeling and function were evaluated with echocardiography, invasive left ventricular hemodynamic measurement, and histological analysis. LncRNA sequencing, chromatin immunoprecipitation assay, and comprehensive identification of RNA-binding proteins by mass spectrometry and Western blot were used to investigate the role of Mhrt779 involved in the antihypertrophic effect induced by EHP. RESULTS: At 1 and 4 weeks after transverse aortic constriction, the EHP group showed less increase in myocardial hypertrophy and lower expression of the Nppa and Myh7 genes than the sedentary group. At 4 weeks after transverse aortic constriction, EHP mice had less pulmonary congestion, smaller left ventricular dimensions and end-diastolic pressure, and a larger left ventricular ejection fraction and maximum pressure change rate than sedentary mice. Quantitative polymerase chain reaction revealed that the long noncoding myosin heavy chain-associated RNA transcript Mhrt779 was one of the markedly upregulated lncRNAs in the EHP group. Silencing of Mhrt779 attenuated the antihypertrophic effect of EHP in mice with transverse aortic constriction and in cultured cardiomyocytes treated with angiotensin II, and overexpression enhanced the antihypertrophic effect. Using chromatin immunoprecipitation assay and quantitative polymerase chain reaction, we found that EHP increased histone 3 trimethylation (H3K4me3 and H3K36me3) at the a4 promoter of Mhrt779. Comprehensive identification of RNA-binding proteins by mass spectrometry and Western blot showed that Mhrt779 can bind SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (Brg1) to inhibit the activation of the histone deacetylase 2 (Hdac2)/phosphorylated serine/threonine kinase (Akt)/phosphorylated glycogen synthase kinase 3ß(p-GSK3ß) pathway induced by pressure overload. CONCLUSIONS: Myocardial hypertrophy preconditioning evoked by exercise increases resistance to pathological stress via an antihypertrophic effect mediated by a signal pathway of Mhrt779/Brg1/Hdac2/p-Akt/p-GSK3ß.

Small Al cluster ion implantation into Si and 4H-SiC.

RATIONALE: Continuously downscaling integrated circuit devices requires fabrication of shallower p-n junctions. The ion implantation approach at low energy is subject to low beam current due to the Coulomb repulsion. To overcome this problem cluster ions can be used for implantation. In comparison with single ions, cluster ions possess lower energy per atom and reduced Coulomb repulsion resulting in high equivalent current. METHODS: In this study to carry out low-energy implantation into single crystalline silicon and 4H-SiC samples we employ Aln - (n = 1-5) clusters with energy in the range of 5-20 keV. The Al clusters are obtained by Cs sputtering of Al rod. Time-of-flight secondary ion mass spectrometry (TOF-SIMS; IONTOF TOF.SIMS-5) is used to study aluminum and oxygen sputter depth profiles for different cluster sizes and implantation energies before and after annealing treatment. RESULTS: A distinguishable effect of the energy per atom in the cluster on reduction of the projected range Rp is revealed. The lowest Rp of 3 ± 1 nm has been achieved in SiC samples at the energy per atom of 1.66 keV. After annealing of Si samples, a considerable change in the Al profiles due to redistribution of Al atoms during motion of the front of recrystallization is observed. The influence of the number of atoms in the cluster at the same energy per atom within the experimental uncertainty is not observed. CONCLUSIONS: The transient effects of the sputtering by the primary ion beam distort the shape of the Al profiles in Si samples. In the case of SiC, due to its relatively lower surface chemical activity, more informative TOF-SIMS depth profiling of the shallow cluster implantation is feasible.

Generation and Characterization of Right Ventricular Myocardial Infarction Induced by Permanent Ligation of the Right Coronary Artery in Mice.

Right ventricular infarction (RVI) is a common presentation in clinical practice. Severe RVI can lead to fatal hemodynamic dysfunction and arrhythmia. In contrast to the extensively used mouse myocardial infarction (MI) model generated by left coronary artery ligation, the RVI mouse model is rarely employed due to the difficulty associated with model generation. Research on the mechanisms and treatment of RVI-induced RV remodeling and dysfunction requires animal models to mimic the pathophysiology of RVI in patients. This study introduces a feasible procedure for RVI model generation in C57BL/6J mice. Further, this model was characterized based on the following: infarct size evaluation at 24 h after MI, assessment of cardiac remodeling and function with echocardiography, RV hemodynamics assessment, and histology of the infarct zone at 4 weeks after RVI. In addition, a coronary vasculature cast was performed to observe the coronary arterial arrangement in RV. This mouse model of RVI would facilitate the research on mechanisms of right heart failure and seek new therapeutic targets of RV remodeling.

Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity.

It has been reported that growth differentiation factor 11 (GDF11) protects against myocardial ischemia/reperfusion (IR) injury, but the underlying mechanisms have not been fully clarified. Considering that GDF11 plays a role in the aging/rejuvenation process and that aging is associated with telomere shortening and cardiac dysfunction, we hypothesized that GDF11 might protect against IR injury by activating telomerase. Human plasma GDF11 levels were significantly lower in acute coronary syndrome patients than in chronic coronary syndrome patients. IR mice with myocardial overexpression GDF11 (oe-GDF11) exhibited a significantly smaller myocardial infarct size, less cardiac remodeling and dysfunction, fewer apoptotic cardiomyocytes, higher telomerase activity, longer telomeres, and higher ATP generation than IR mice treated with an adenovirus carrying a negative control plasmid. Furthermore, mitochondrial biogenesis-related proteins and some antiapoptotic proteins were significantly upregulated by oe-GDF11. These cardioprotective effects of oe-GDF11 were significantly antagonized by BIBR1532, a specific telomerase inhibitor. Similar effects of oe-GDF11 on apoptosis and mitochondrial energy biogenesis were observed in cultured neonatal rat cardiomyocytes, whereas GDF11 silencing elicited the opposite effects to oe-GDF11 in mice. We concluded that telomerase activation by GDF11 contributes to the alleviation of myocardial IR injury through enhancing mitochondrial biogenesis and suppressing cardiomyocyte apoptosis.

Bibliometric Study of Sodium Glucose Cotransporter 2 Inhibitors in Cardiovascular Research.

BACKGROUND: An increasing number of studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors, initially used as antidiabetic agents, have cardiovascular (CV) benefits. However, few bibliometric analyses have examined this field systematically. Our study aimed to visualize the publications to determine the trends and hotspots in CV research on SGLT2 inhibitors. METHODS: Publications on SGLT2 inhibitors in cardiovascular research were retrieved from the Web of Science Core Collection. Microsoft Excel 2019, VOSviewer, and CiteSpace V were used to analyze and plot the references. RESULTS: On July 3, 2020, 1509 records of CV research on SGLT2 inhibitors published from 2013 to 2020 were retrieved. Nearly half were authored by American scholars, and most were published in Diabetes Obesity Metabolism, Cardiovascular Diabetology, and Diabetes Therapy. The USA was the leading driving force, with a strong academic reputation in this area. Inzucchi SE published the most related articles, while Neal B was cited the most frequently. All the top 10 co-cited references were in the leading co-cited journal, The New England Journal of Medicine. "Atherosclerotic cardiovascular event" was the leading research hotspot. The keywords "cardiac metabolism," "heart failure hospitalization," and "heart failure with preserved ejection fraction" appeared most recently as research frontiers. CONCLUSION: Most studies focused on clinical trial outcomes, such as cardiovascular death and heart failure (HF) hospitalization. The mechanisms of SGLT2 inhibitors, especially those related to cardiac metabolism, may soon become hotspots and should be closely monitored.