Endothelial specific prolyl hydroxylase domain-containing protein 2 deficiency attenuates aging-related obesity and exercise intolerance.

Obesity and exercise intolerance greatly reduce the life quality of older people. Prolyl hydroxylase domain-containing protein 2 (PHD2) is an important enzyme in modulating hypoxia-inducible factor-alpha (HIF) protein. Using vascular endothelial cell-specific PHD2 gene knockout (PHD2 ECKO) mice, we investigated the role of endothelial PHD2 in aging-related obesity and exercise capacity. Briefly, PHD2 ECKO mice were obtained by crossing PHD2-floxed mice with VE-Cadherin (Cdh5)-Cre transgenic mice. The effect of PHD2 ECKO on obesity and exercise capacity in PHD2 ECKO mice and control PHD2f/f mice were determined in young mice (6 to 7 months) and aged mice (16-18 months). We found that aged PHD2 ECKO mice, but not young mice, exhibited a lean phenotype, characterized by lower fat mass, and its ratio to lean weight, body weight, or tibial length, while their food uptake was not reduced compared with controls. Moreover, as compared with aged control mice, aged PHD2 ECKO mice exhibited increased oxygen consumption at rest and during exercise, and the maximum rate of oxygen consumption (VO2 max) during exercise. Furthermore, as compared with corresponding control mice, both young and aged PHD2 ECKO mice demonstrated improved glucose tolerance and lower insulin resistance. Together, these data demonstrate that inhibition of vascular endothelial PHD2 signaling significantly attenuates aging-related obesity, exercise intolerance, and glucose intolerance.

p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD. METHODS: We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p534KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF. RESULTS: Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice, as well as in p534KR mice after transverse aortic constriction. In vitro, p534KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice. CONCLUSIONS: Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.

TIGAR Deficiency Blunts Angiotensin-II-Induced Cardiac Hypertrophy in Mice.

Hypertension is the key contributor to pathological cardiac hypertrophy. Growing evidence indicates that glucose metabolism plays an essential role in cardiac hypertrophy. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism in pressure overload-induced cardiac remodeling. In the present study, we investigated the role of TIGAR in cardiac remodeling during Angiotensin II (Ang-II)-induced hypertension. Wild-type (WT) and TIGAR knockout (KO) mice were infused with Angiotensin-II (Ang-II, 1 µg/kg/min) via mini-pump for four weeks. The blood pressure was similar between the WT and TIGAR KO mice. The Ang-II infusion resulted in a similar reduction of systolic function in both groups, as evidenced by the comparable decrease in LV ejection fraction and fractional shortening. The Ang-II infusion also increased the isovolumic relaxation time and myocardial performance index to the same extent in WT and TIGAR KO mice, suggesting the development of similar diastolic dysfunction. However, the knockout of TIGAR significantly attenuated hypertension-induced cardiac hypertrophy. This was associated with higher levels of fructose 2,6-bisphosphate, PFK-1, and Glut-4 in the TIGAR KO mice. Our present study suggests that TIGAR is involved in the control of glucose metabolism and glucose transporters by Ang-II and that knockout of TIGAR attenuates the development of maladaptive cardiac hypertrophy.

A hypernetwork-based urn model for explaining collective dynamics.

The topological characterization of complex systems has significantly contributed to our understanding of the principles of collective dynamics. However, the representation of general complex networks is not enough for explaining certain problems, such as collective actions. Considering the effectiveness of hypernetworks on modeling real-world complex networks, in this paper, we proposed a hypernetwork-based Pólya urn model that considers the effect of group identity. The mathematical deduction and simulation experiments show that social influence provides a strong imitation environment for individuals, which can prevent the dynamics from being self-correcting. Additionally, the unpredictability of the social system increases with growing social influence, and the effect of group identity can moderate market inequality caused by individual preference and social influence. The present work provides a modeling basis for a better understanding of the logic of collective dynamics.

Inhibition of NK1.1 signaling attenuates pressure overload-induced heart failure, and consequent pulmonary inflammation and remodeling.

Background: Inflammation contributes to heart failure (HF) development, the progression from left ventricular failure to pulmonary remodeling, and the consequent right ventricular hypertrophy and failure. NK1.1 plays a critical role in Natural killer (NK) and NK T (NKT) cells, but the role of NK1.1 in HF development and progression is unknown. Methods: We studied the effects of NK1.1 inhibition on transverse aortic constriction (TAC)-induced cardiopulmonary inflammation, HF development, and HF progression in immunocompetent male mice of C57BL/6J background. Results: We found that NK1.1+ cell-derived interferon gamma+ (IFN-γ+) was significantly increased in pulmonary tissues after HF. In addition, anti-NK1.1 antibodies simultaneously abolished both NK1.1+ cells, including the NK1.1+NK and NK1.1+NKT cells in peripheral blood, spleen, and lung tissues, but had no effect on cardiopulmonary structure and function under control conditions. However, systemic inhibition of NK1.1 signaling by anti-NK1.1 antibodies significantly rescued mice from TAC-induced left ventricular inflammation, fibrosis, and failure. Inhibition of NK1.1 signaling also significantly attenuated TAC-induced pulmonary leukocyte infiltration, fibrosis, vessel remodeling, and consequent right ventricular hypertrophy. Moreover, inhibition of NK1.1 signaling significantly reduced TAC-induced pulmonary macrophage and dendritic cell infiltration and activation. Conclusions: Our data suggest that inhibition of NK1.1 signaling is effective in attenuating systolic overload-induced cardiac fibrosis, dysfunction, and consequent pulmonary remodeling in immunocompetent mice through modulating the cardiopulmonary inflammatory response.

The Effect of Fangcang Shelter Hospitals under Resource Constraints on the Spread of Epidemics.

Since the outbreak of the COVID-19 pandemic, Fangcang shelter hospitals have been built and operated in several cities, and have played a huge role in epidemic prevention and control. How to use medical resources effectively in order to maximize epidemic prevention and control is a big challenge that the government should address. In this paper, a two-stage infectious disease model was developed to analyze the role of Fangcang shelter hospitals in epidemic prevention and control, and examine the impact of medical resources allocation on epidemic prevention and control. Our model suggested that the Fangcang shelter hospital could effectively control the rapid spread of the epidemic, and for a very large city with a population of about 10 million and a relative shortage of medical resources, the model predicted that the final number of confirmed cases could be only 3.4% of the total population in the best case scenario. The paper further discusses the optimal solutions regarding medical resource allocation when medical resources are either limited or abundant. The results show that the optimal allocation ratio of resources between designated hospitals and Fangcang shelter hospitals varies with the amount of additional resources. When resources are relatively sufficient, the upper limit of the proportion of makeshift hospitals is about 91%, while the lower limit decreases with the increase in resources. Meanwhile, there is a negative correlation between the intensity of medical work and the proportion of distribution. Our work deepens our understanding of the role of Fangcang shelter hospitals in the pandemic and provides a reference for feasible strategies by which to contain the pandemic.

Spatiotemporal and Seasonal Trends of Class A and B Notifiable Infectious Diseases in China: Retrospective Analysis.

BACKGROUND: China is the most populous country globally and has made significant achievements in the control of infectious diseases over the last decades. The 2003 SARS epidemic triggered the initiation of the China Information System for Disease Control and Prevention (CISDCP). Since then, numerous studies have investigated the epidemiological features and trends of individual infectious diseases in China; however, few considered the changing spatiotemporal trends and seasonality of these infectious diseases over time. OBJECTIVE: This study aims to systematically review the spatiotemporal trends and seasonal characteristics of class A and class B notifiable infectious diseases in China during 2005-2020. METHODS: We extracted the incidence and mortality data of 8 types (27 diseases) of notifiable infectious diseases from the CISDCP. We used the Mann-Kendall and Sen's methods to investigate the diseases' temporal trends, Moran I statistic for their geographical distribution, and circular distribution analysis for their seasonality. RESULTS: Between January 2005 and December 2020, 51,028,733 incident cases and 261,851 attributable deaths were recorded. Pertussis (P=.03), dengue fever (P=.01), brucellosis (P=.001), scarlet fever (P=.02), AIDS (P<.001), syphilis (P<.001), hepatitis C (P<.001) and hepatitis E (P=.04) exhibited significant upward trends. Furthermore, measles (P<.001), bacillary and amebic dysentery (P<.001), malaria (P=.04), dengue fever (P=.006), brucellosis (P=.03), and tuberculosis (P=.003) exhibited significant seasonal patterns. We observed marked disease burden-related geographic disparities and heterogeneities. Notably, high-risk areas for various infectious diseases have remained relatively unchanged since 2005. In particular, hemorrhagic fever and brucellosis were largely concentrated in Northeast China; neonatal tetanus, typhoid and paratyphoid, Japanese encephalitis, leptospirosis, and AIDS in Southwest China; BAD in North China; schistosomiasis in Central China; anthrax, tuberculosis, and hepatitis A in Northwest China; rabies in South China; and gonorrhea in East China. However, the geographical distribution of syphilis, scarlet fever, and hepatitis E drifted from coastal to inland provinces during 2005-2020. CONCLUSIONS: The overall infectious disease burden in China is declining; however, hepatitis C and E, bacterial infections, and sexually transmitted infections continue to multiply, many of which have spread from coastal to inland provinces.

Conformity effect on the evolution of cooperation in signed networks.

Human behaviors are often subject to conformity, but little research attention has been paid to social dilemmas in which players are assumed to only pursue the maximization of their payoffs. The present study proposed a generalized prisoner dilemma model in a signed network considering conformity. Simulation shows that conformity helps promote the imitation of cooperative behavior when positive edges dominate the network, while negative edges may impede conformity from fostering cooperation. The logic of homophily and xenophobia allows for the coexistence of cooperators and defectors and guides the evolution toward the equality of the two strategies. We also find that cooperation prevails when individuals have a higher probability of adjusting their relation signs, but conformity may mediate the effect of network adaptation. From a population-wide view, network adaptation and conformity are capable of forming the structures of attractors or repellers.

IL-12α deficiency attenuates pressure overload-induced cardiac inflammation, hypertrophy, dysfunction, and heart failure progression.

IL-12α plays an important role in modulating inflammatory response, fibroblast proliferation and angiogenesis through modulating macrophage polarization or T cell function, but its effect on cardiorespiratory fitness is not clear. Here, we studied the effect of IL-12α on cardiac inflammation, hypertrophy, dysfunction, and lung remodeling in IL-12α gene knockout (KO) mice in response to chronic systolic pressure overload produced by transverse aortic constriction (TAC). Our results showed that IL-12α KO significantly ameliorated TAC-induced left ventricular (LV) failure, as evidenced by a smaller decrease of LV ejection fraction. IL-12α KO also exhibited significantly attenuated TAC-induced increase of LV weight, left atrial weight, lung weight, right ventricular weight, and the ratios of them in comparison to body weight or tibial length. In addition, IL-12α KO showed significantly attenuated TAC-induced LV leukocyte infiltration, fibrosis, cardiomyocyte hypertrophy, and lung inflammation and remodeling (such as lung fibrosis and vessel muscularization). Moreover, IL-12α KO displayed significantly attenuated TAC-induced activation of CD4+ T cells and CD8+ T cells in the lung. Furthermore, IL-12α KO showed significantly suppressed accumulation and activation of pulmonary macrophages and dendritic cells. Taken together, these findings indicate that inhibition of IL-12α is effective in attenuating systolic overload-induced cardiac inflammation, heart failure development, promoting transition from LV failure to lung remodeling and right ventricular hypertrophy.

P53 Acetylation Exerts Critical Roles In Pressure Overload Induced Coronary Microvascular Dysfunction and Heart Failure.

Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure with preserved ejection fraction. At this point, there are no proven treatments for CMD. We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98/117/161/162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve coronary microvascular dysfunction and prevent the progression of hypertensive cardiac hypertrophy and heart failure. Wild-type (WT) and p534KR mice were subjected to pressure overload (PO) by transverse aortic constriction to induce cardiac hypertrophy and heart failure (HF). Echocardiography measurements revealed improved cardiac function together with reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve (CFR) were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and glucose transporters, as well as the level of fructose-2,6-biphosphate; increased PFK-1 activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice as well as in p534KR mice after TAC. In vitro, p534KR significantly improved endothelial cell (EC) glycolytic function and mitochondrial respiration, and enhanced EC proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved CFR and rescued cardiac dysfunction in SIRT3 KO mice. Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling, and may provide a promising approach to improve hypertension-induced coronary microvascular dysfunction (CMD) and to prevent the transition of cardiac hypertrophy to heart failure.

A memetic algorithm for finding multiple subgraphs that optimally cover an input network.

Finding dense subgraphs is a central problem in graph mining, with a variety of real-world application domains including biological analysis, financial market evaluation, and sociological surveys. While a series of studies have been devoted to finding subgraphs with maximum density, the problem of finding multiple subgraphs that best cover an input network has not been systematically explored. The present study discusses a variant of the densest subgraph problem and presents a mathematical model for optimizing the total coverage of an input network by extracting multiple subgraphs. A memetic algorithm that maximizes coverage is proposed and shown to be both effective and efficient. The method is applied to real-world networks. The empirical meaning of the optimal sampling method is discussed.

A Prospective Study on Resilience Among Children with Different Migrant and Left-behind Trajectories.

Parental migration has been an important predictor of children's psychological resilience. The present study discusses the effect of parental migration on children's resilience in rural western China from a dynamic viewpoint. Using sequence analysis, this study investigates children's entire migration trajectory over the course of childhood (ages 1-12) and identifies the typical patterns of the dynamic family structure associated with parental migration: continuously nonmigrant (N = 4,238), continuously migrant (N = 923), continuously left behind by one parent (N = 872), continuously left behind by both parents (N = 796) and frequent transition between migrant or left-behind statuses (N = 1,624). The results show that the trajectories of left-behind status and transition have a significant negative impact on children's resilience, which demonstrates that both the effects of parent-child separation and family instability compromise children's psychological functioning. Family resources can buffer these negative effects, but they work asymmetrically across different groups of children. Family economic resources serve as a significant protective factor among children continuously left behind by both parents, while family social resources are more protective for children in unstable families. Supplementary Information: The online version contains supplementary material available at 10.1007/s12187-022-09945-1.

Knockout of TIGAR enhances myocardial phosphofructokinase activity and preserves diastolic function in heart failure.

Hypertension is an important risk factor in the pathogenesis of diastolic dysfunction. Growing evidence indicates that glucose metabolism plays an essential role in diastolic dysfunction. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism and heart failure (HF). In the present study, we investigated the role of TIGAR in diastolic function and cardiac fibrosis during pressure overload (PO)-induced HF. WT mice subjected to transverse aortic constriction (TAC), a commonly used method to induce diastolic dysfunction, exhibited diastolic dysfunction as evidenced by increased E/A ratio and E/E' ratio when compared to its sham controls. This was accompanied by increased cardiac interstitial fibrosis. In contrast, the knockout of TIGAR attenuated PO-induced diastolic dysfunction and interstitial fibrosis. Mechanistically, the levels of glucose transporter Glut-1, Glut-4, and key glycolytic enzyme phosphofructokinase 1 (PFK-1) were significantly elevated in TIGAR KO subjected to TAC as compared to that of WT mice. Knockout of TIGAR significantly increased fructose 2,6-bisphosphate levels and phosphofructokinase activity in mouse hearts. In addition, PO resulted in a significant increase in perivascular fibrosis and endothelial activation in the WT mice, but not in the TIGAR KO mice. Our present study suggests a necessary role of TIGAR-mediated glucose metabolism in PO-induced cardiac fibrosis and diastolic dysfunction.

TIGAR deficiency sensitizes angiotensin-II-induced renal fibrosis and glomerular injury.

Angiotensin II (Ang-II) is one of the major contributors to the progression of renal fibrosis, inflammation, glomerular injury, and chronic kidney disease. Emerging evidence suggests that renal glycolysis plays an important role in renal fibrosis and injury. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glycolysis. In the present study, we investigated the role of TIGAR in renal glycolysis, fibrosis, and glomerular injury during Ang-II-induced hypertension. Wild-type (WT) and TIGAR knockout (KO) mice were infused with Ang-II (1 µg/kg/min) via mini-pumps for 4 weeks. The mean arterial pressure was similar between the WT and TIGAR KO mice, associated with a comparable increase in plasma creatinine level. Ang-II infusion resulted in a significant increase in renal interstitial fibrosis and more mesangial expansion and collapsed glomerular structure in the TIGAR KO mice. These were associated with elevated expression of hypoxia-inducible factor-1 alpha, glycolytic enzymes, and transforming growth factor beta 1 in the TIGAR KO mice after Ang-II infusion when compared to that of the WT mice. The coupled-enzyme method revealed that PFK-1 activity was similarly increased in WT and TIGAR KO mice after Ang-II infusion. Our present study suggests that TIGAR is involved in Ang-II-induced renal fibrosis and glomerular injury, although it has little effect on blood pressure and renal function. Knockout of TIGAR sensitizes Ang-II-induced renal fibrosis and injury. This study provides new insights into the role of TIGAR in renal metabolism and pathological remodeling during Ang-II-induced hypertension.

The Effect of Local and Global Interventions on Epidemic Spreading.

Epidemic spreading causes severe challenges to the global public health system, and global and local interventions are considered an effective way to contain such spreading, including school closures (local), border control (global), etc. However, there is little study on comparing the efficiency of global and local interventions on epidemic spreading. Here, we develop a new model based on the Susceptible-Exposed-Infectious-Recovered (SEIR) model with an additional compartment called "quarantine status". We simulate various kinds of outbreaks and interventions. Firstly, we predict, consistent with previous studies, interventions reduce epidemic spreading to 16% of its normal level. Moreover, we compare the effect of global and local interventions and find that local interventions are more effective than global ones. We then study the relationships between incubation period and interventions, finding that early implementation of rigorous intervention significantly reduced the scale of the epidemic. Strikingly, we suggest a Pareto optimal in the intervention when resources were limited. Finally, we show that combining global and local interventions is the most effective way to contain the pandemic spreading if initially infected individuals are concentrated in localized regions. Our work deepens our understandings of the role of interventions on the pandemic, and informs an actionable strategy to contain it.

Regulatory role of TIGAR on endothelial metabolism and angiogenesis.

Endothelial glycolytic metabolism plays an important role in the process of angiogenesis. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a significant mediator of cellular energy homeostasis. However, the role of TIGAR in endothelial metabolism, angiogenesis, and coronary flow reserve (CFR) has not been studied. The present study investigated whether knockout (KO) of TIGAR improves endothelial glycolytic function and angiogenesis. In vitro, aortic endothelial cells (ECs) from TIGAR KO mice exhibited increased expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform-3 (PFKFB3) and increased glycolytic function. These were accompanied by increased mitochondrial basal/maximal respiration and ATP production. Furthermore, knockout of TIGAR in ECs enhanced endothelial proliferation, migration, and tube formation. Knockout of TIGAR also significantly increased aortic sprouting ex vivo. In vivo, knockout of TIGAR increased the expression of proangiogenic factor, angiopoietin-1 (Ang-1) in mouse hearts. Knockout of TIGAR also significantly increased coronary capillary density with enhanced CFR in these hearts. Furthermore, TIGAR KO mice subjected to pressure overload (PO), a common model to study angiogenesis and cardiac hypertrophy, exhibited elevated expression of Ang-1, VEGF, and PFKFB3 than that of the wild-type (WT) mice. WT mice subjected to PO exhibited a significant reduction of coronary capillary density and impaired CFR, but TIGAR KO mice did not. In addition, knockout of TIGAR blunted TAC-induced cardiac hypertrophy and dysfunction seen in the WT mice. In conclusion, knockout of TIGAR improves endothelial angiogenetic capabilities by enhancing the endothelial glycolytic function, mitochondrial respiration, and proangiogenic signaling, which leads to increased coronary capillary density and vascular function and protects against chronic stress.

Sirtuin 3 Alleviates Diabetic Cardiomyopathy by Regulating TIGAR and Cardiomyocyte Metabolism.

Background Impairment of glycolytic metabolism is suggested to contribute to diabetic cardiomyopathy. In this study, we explored the roles of SIRT3 (Sirtuin 3) on cardiomyocyte glucose metabolism and cardiac function. Methods and Results Exposure of H9c2 cardiomyocyte cell lines to high glucose (HG) (30 mmol/L) resulted in a gradual decrease in SIRT3 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) expression together with increases in p53 acetylation and TP53-induced glycolysis and apoptosis regulator (TIGAR) expression. Glycolysis was significantly reduced in the cardiomyocyte exposed to HG. Transfection with adenovirus-SIRT3 significantly increased PFKFB3 expression and reduced HG-induced p53 acetylation and TIGAR expression. Overexpression of SIRT3 rescued impaired glycolysis and attenuated HG-induced reactive oxygen species formation and apoptosis. Knockdown of TIGAR in cardiomyocytes by using siRNA significantly increased PFKFB3 expression and glycolysis under hyperglycemic conditions. This was accompanied by a significant suppression of HG-induced reactive oxygen species formation and apoptosis. In vivo, overexpression of SIRT3 by an intravenous jugular vein injection of adenovirus-SIRT3 resulted in a significant reduction of p53 acetylation and TIGAR expression together with upregulation of PFKFB3 expression in the heart of diabetic db/db mice at day 14. Overexpression of SIRT3 further reduced reactive oxygen species formation and blunted microvascular rarefaction in the diabetic db/db mouse hearts. Overexpression of SIRT3 significantly blunted cardiac fibrosis and hypertrophy and improved cardiac function at day 14. Conclusions Our study demonstrated that SIRT3 attenuated diabetic cardiomyopathy via regulating p53 acetylation and TIGAR expression. Therefore, SIRT3 may be a novel target for abnormal energy metabolism in diabetes mellitus.

A Sex-Specific Role of Endothelial Sirtuin 3 on Blood Pressure and Diastolic Dysfunction in Female Mice.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is characterized by a diastolic dysfunction and is highly prevalent in aged women. Our study showed that ablation of endothelial Sirtuin 3 (SIRT3) led to diastolic dysfunction in male mice. However, the sex-specific role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female mice remains to be investigated. METHODS AND RESULTS: In this study, we demonstrate that the ablation of endothelial SIRT3 in females elevated blood pressure as compared with control female mice. Diastolic function measurement also showed that the isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were significantly increased, whereas the E' velocity/A' velocity (E'/A') ratio was reduced in the endothelial-specific SIRT3 knockout (SIRT3 ECKO) female mice. To further investigate the regulatory role of endothelial SIRT3 on blood pressure and diastolic dysfunction in metabolic stress, SIRT3 ECKO female mice were fed a normal diet and high-fat diet (HFD) for 20 weeks. The knockout of endothelial SIRT3 resulted in an increased blood pressure in female mice fed with an HFD. Intriguingly, SIRT3 ECKO female mice + HFD exhibited impaired coronary flow reserve (CFR) and more severe diastolic dysfunction as evidenced by an elevated IVRT as compared with control female mice + HFD. In addition, female SIRT3 ECKO mice had higher blood pressure and diastolic dysfunction as compared to male SIRT3 ECKO mice. Moreover, female SIRT3 ECKO mice + HFD had an impaired CFR and diastolic dysfunction as compared to male SIRT3 ECKO mice + HFD. CONCLUSIONS: These results implicate a sex-specific role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice. Deficiency of endothelial SIRT3 may be responsible for a diastolic dysfunction in aged female.

SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis.

BACKGROUND: Sirtuin 3 (SIRT3) has a crucial role in the cardiovascular diseases. Our previous study revealed that SIRT3 knockout (SIRT3KO) promoted cardiac pericyte-fibroblast transition. In this study, we investigated the involvement of pericyte and iron in angiotensin II (Ang-II)-mediated renal fibrosis in the SIRT3KO mice. METHODS AND RESULTS: NG2-DsRed mice and NG2-DsRed-SIRT3 knockout (SIRT3KO) mice were infused with saline or Ang-II (1000 ng/kg/min) for 4 weeks. Renal fibrosis, iron content and reactive oxygen species (ROS) were measured. Masson's trichrome staining showed that SIRT3KO enhanced Ang-II-induced renal fibrosis. Immunostaining showed that Ang-II treatment increased the number of NG2-DsRed+ cells in the kidney, and SIRT3KO further enhanced NG2-DsRed+ cells. Moreover, SIRT3KO promoted pericyte differentiation into fibroblasts as evidenced by co-staining NG2-DsRed/FSP-1. Furthermore, DsRed/FSP-1+ and DsRed/transforming growth factor-ß1 (TGF-ß1)+ fibroblasts were elevated by SIRT3KO after Ang-II infusion. Ang-II-induced collagen I and TGF-ß1 expression was also enhanced in the SIRT3KO mice. SIRT3KO significantly exacerbated Ang-II-induced iron accumulation. This was accompanied by an increase in acetyl-p53, HO-1 and FPN expression. Further, SIRT3KO sensitized Ang-II-induced upregulation of p47phox and gp91phox together with increased ROS formation in the kidney. CONCLUSION: Our study suggests that SIRT3 deficiency sensitized Ang-II-induced renal fibrosis by the mechanisms involved in promoting differentiation of pericytes into fibroblasts, exacerbating iron overload and accelerating NADPH oxidase-derived ROS formation.

Histone Acetyltransferase p300 Inhibitor Improves Coronary Flow Reserve in SIRT3 (Sirtuin 3) Knockout Mice.

Background Coronary microvascular dysfunction is common in patients of myocardial infarction with non-obstructive coronary artery disease. Coronary flow reserve (CFR) reflects coronary microvascular function and is a powerful independent index of coronary microvascular dysfunction and heart failure. Our previous studies showed that knockout of SIRT3 (Sirtuin 3) decreased CFR and caused a diastolic dysfunction. Few studies focus on the treatment of impaired CFR and heart failure. In the present study, we explored the role of C646, a histone acetyltransferase p300 inhibitor, in regulating CFR and cardiac remodeling in SIRT3 knockout (SIRT3KO) mice. Methods and Results After treating with C646 for 14 days, CFR, pulse-wave velocity, and cardiac function were measured in SIRT3KO mice. SIRT3KO mice treated with C646 showed a significant improvement of CFR, pulse-wave velocity, ejection fraction, and fractional shortening. Treatment with C646 reversed pre-existing cardiac fibrosis, hypertrophy, and capillary rarefaction in SIRT3KO mice. Mechanistically, knockout of Sirtuin 3 resulted in significant increases in p300 expression and H3K56 acetylation. Treatment with C646 significantly reduced levels of p300 and H3K56 acetylation in SIRT3KO mice. Furthermore, treatment with C646 increased endothelial nitric oxide synthase expression and reduced arginase II expression and activity. The expression of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and VCAM-1 (vascular cell adhesion molecule 1) was also significantly suppressed by C646 treatment in SIRT3KO mice. Conclusions C646 treatment attenuated p300 and H3K56 acetylation and improved arterial stiffness and CFR via improvement of endothelial cell (EC) dysfunction and suppression of NF-κB.