Abstract 263: A Decline in Kidney-derived Protein Klotho Contributes to Aging-related Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhongjie Sun ◽  
Kai Chen
Keyword(s):  
Heart Failure ◽  
Therapeutic Strategy ◽  
Contractile Function ◽  
Heart Function ◽  
Heart Diseases ◽  
Daily Injection ◽  
Aged Mice ◽  
Adult Mice ◽  
Effective Therapeutic Strategy ◽  
Klotho Protein

Background & Objective: The heart function declines in the aged population. At age 80 years, LV contractile function is less than half of what it was at age 20 years. Aging is a recognized risk factor for heart diseases. For instance, the prevalence of heart disease increases with age. The mortality from heart diseases is higher in the aged than in the young population. Klotho is a recently discovered anti-aging gene that is primarily expressed in kidneys. The secreted Klotho is released into blood. The objective of this study is to investigate if a decline serum Klotho levels contributes to aging-related heart failure. Method & Results: The results showed that ejection fraction, stroke volume and cardiac output were decreased in aged mice (24 months) vs. the adult mice (10 months), indicating that aging impairs heart function. The serum level of Klotho was decreased significantly in aged mice. Interestingly, daily injection of recombinant Klotho protein rescued the aging-related decline in heart function. Mutation of Klotho gene ( KL -/- ) resulted in heart failure which was associated with a significant increase in serum phosphate levels (hyperphosphatemia). Low phosphate diet delayed but did not prevent the development of heart failure in male KL -/- mice, suggesting that hyperphosphatemia partially contributes to Klotho deficiency-induced heart failure. Unfortunately, low phosphate diet failed to improve heart failure in female KL -/- mice. Interestingly, administration of estrogen decreased hyperphosphatemia and delayed the development of heart failure in KL -/- although it did not prevent Klotho deficiency-induced heart failure. Therefore, Conclusion: Klotho deficiency contributes to aging-related heart failure. Hyperphosphatemia accelerated the development of Klotho deficiency-induced heart failure. Administration of recombinant Klotho protein is an effective therapeutic strategy for heart aging. (supported by NIH R01 HL118558, AG049780, DK093403).

Abstract 19292: KLF4 Regulates Mitochondrial Homeostasis in the Heart

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Xudong Liao ◽  
Mukesh Jain
Keyword(s):  
Heart Failure ◽  
Mitochondrial Biogenesis ◽  
Transcriptional Control ◽  
Heart Function ◽  
Heart Diseases ◽  
Pressure Overload ◽  
Premature Mortality ◽  
Mitochondrial Homeostasis ◽  
Adult Mice ◽  
Mitochondrial Heterogeneity

Mitochondrial homeostasis is critical for heart function and mitochondrial dysfunction contributes to numerous heart diseases such as heart failure. Our previous work indicates that mice with cardiomyocyte-restricted deficiency of KLF4 develop heart failure precipitously in response to pressure-overload but the underlying mechanisms remain unknown. We hypothesized that KLF4 may regulate mitochondrial function in the heart. Here we show that KLF4 governs mitochondrial biogenesis, metabolic function, dynamics and autophagic clearance. Adult mice with cardiac-specific KLF4 deficiency develop cardiac dysfunction with aging or in response to pressure overload characterized by reduced myocardial ATP levels, elevated ROS, and marked alterations in mitochondrial heterogeneity and alignment. Studies in mitochondria isolated from KLF4-deficient hearts revealed reduced respiration rate likely due to defects in ETC Complex I. Further, embryonic cardiac KLF4 deletion resulted in postnatal premature mortality, impaired mitochondrial biogenesis, and altered mitochondrial maturation. Mechanistically, we show that KLF4 binds to, cooperates with, and is requisite for optimal function of the ERR/PGC-1 transcriptional regulatory module on metabolic and mitochondrial targets. Finally, KLF4 also regulates autophagy through transcriptional control of a broad array of autophagy genes in cardiomyocytes. Collectively, these findings identify KLF4 as a nodal transcriptional regulator of mitochondrial homeostasis.

scholarly journals Agrin promotes coordinated therapeutic processes leading to improved cardiac repair in pigs

2019 ◽  
Author(s):  
Andrea Baehr ◽  
Kfir Baruch Umansky ◽  
Elad Bassat ◽  
Katharina Klett ◽  
Victoria Jurisch ◽  
...  
Keyword(s):  
Heart Failure ◽  
Single Dose ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Life Quality ◽  
Cardiac Regeneration ◽  
Adult Mice

AbstractIschemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We have recently reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Here, we tested the therapeutic potential of Agrin in a preclinical porcine model, comprising either 3 or 28 days (d) reperfusion period. We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. Single dose of rhAgrin resulted in significant improvement in heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiment along with complementary murine MI studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin’s mechanisms of action. We conclude that a single dose of Agrin is capable of reducing ischemia reperfusion injury and improving cardiac function, demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure.

Carvedilol Inhibits Matrix Metalloproteinase-2 Activation in Experimental Autoimmune Myocarditis: Possibilities of Cardioprotective Application

2017 ◽  
Vol 23 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Monika Skrzypiec-Spring ◽  
Katarzyna Haczkiewicz ◽  
Agnieszka Sapa ◽  
Tomasz Piasecki ◽  
Joanna Kwiatkowska ◽  
...  
Keyword(s):  
Heart Failure ◽  
Troponin I ◽  
Heart Function ◽  
Heart Diseases ◽  
Acute Myocarditis ◽  
Study Groups ◽  
Matrix Metalloproteinase 2 ◽  
Autoimmune Myocarditis ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Aims: Acute myocarditis is a potentially lethal inflammatory heart disease that frequently precedes the development of dilated cardiomyopathy and subsequent heart failure. At present, there is no effective standardized therapy for acute myocarditis, besides the optimal care of heart failure and arrhythmias in accordance with evidence-based guidelines and specific etiology-driven therapy for infectious myocarditis. Carvedilol has been shown to be cardioprotective by reducing cardiac pro-inflammatory cytokines present in oxidative stress in certain heart diseases. However, effects of carvedilol administration in acute myocarditis with its impact on matrix metalloproteinases’ (MMPs) activation have not been elucidated. Methods and Results: Carvedilol in 3 doses (2, 10, and 30 mg/kg) was given daily to 3 study groups of rats (n = 8) with experimental autoimmune myocarditis by gastric gavage for 3 weeks. In comparison to untreated rats (n = 8) with induced myocarditis, carvedilol significantly prevented the left ventricle enlargement and/or systolic dysfunction depending on the dose in study groups. Performed zymography showed enhanced MMP-2 activity in untreated rats, while carvedilol administration reduced alterations. This was accompanied by prevention of troponin I release and myofilaments degradation in cardiac muscle tissue. Additionally, severe inflammatory cell infiltration was detected in the nontreated group. Carvedilol in all doses tested, had no impact on severity of inflammation. The severity of inflammation did not differ between study groups and in relation to the untreated group. Conclusions: The protective effects of carvedilol on heart function observed in the acute phase of experimental autoimmune myocarditis seem to be associated with its ability to decrease MMP-2 activity and subsequently prevent degradation of myofilaments and release of troponin I while not related to suppression of inflammation.

scholarly journals Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs

Circulation ◽  
2020 ◽  
Vol 142 (9) ◽  
pp. 868-881 ◽  
Author(s):  
Andrea Baehr ◽  
Kfir Baruch Umansky ◽  
Elad Bassat ◽  
Victoria Jurisch ◽  
Katharina Klett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Single Dose ◽  
Matrix Protein ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Extracellular Matrix Protein ◽  
Number Of Patients

Background: Ischemic heart diseases are leading causes of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a large number of patients with MI develop chronic heart failure over time. We previously reported that a fragment of the extracellular matrix protein agrin promotes cardiac regeneration after MI in adult mice. Methods: To test the therapeutic potential of agrin in a preclinical porcine model, we performed ischemia–reperfusion injuries using balloon occlusion for 60 minutes followed by a 3-, 7-, or 28-day reperfusion period. Results: We demonstrated that local (antegrade) delivery of recombinant human agrin to the infarcted pig heart can target the affected regions in an efficient and clinically relevant manner. A single dose of recombinant human agrin improved heart function, infarct size, fibrosis, and adverse remodeling parameters 28 days after MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression, and cell cycle reentry as agrin’s mechanisms of action. Conclusions: A single dose of agrin is capable of reducing ischemia–reperfusion injury and improving heart function, demonstrating that agrin could serve as a therapy for patients with acute MI and potentially heart failure.

scholarly journals A long noncoding RNA CHAIR protects the heart from pathological stress

2020 ◽  
Vol 134 (13) ◽  
pp. 1843-1857
Author(s):  
Yanxia Qian ◽  
Mingming Zhang ◽  
Ningtian Zhou ◽  
Xiaohan Xu ◽  
Jiahui Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Development ◽  
Noncoding Rna ◽  
Heart Function ◽  
Heart Diseases ◽  
Binding Activity ◽  
Epigenetic Mechanism ◽  
Protein Coding ◽  
Dna Binding Activity ◽  
Heart Failure Progression

Abstract Mammalian genomes have been found to be extensively transcribed. In addition to classic protein coding genes, a large numbers of long noncoding genes (lncRNAs) have been identified, while their functions, especially in heart diseases, remain to be established. We hypothesized that heart failure progression is controlled by tissue-specific lncRNAs. In the present study, we found that the cardiac-enriched lncRNA 4632428C04Rik, named as cardiomyocyte hypertrophic associated inhibitory RNA (CHAIR), is dynamically regulated during heart development, is expressed at low levels in embryonic hearts and accumulated at high levels in adult hearts. More interestingly, the lncRNA was down-regulated during cardiac hypertrophy and failure both in mice and humans. Importantly, loss of lncRNA CHAIR has no effects on normal hearts, whereas it results in accelerated heart function decline, increased hypertrophy, and exacerbated heart failure in response to stress. In contrast, restoring the expression of lncRNA CHAIR rescued the hearts from hypertrophy and failure. DNMT3A was recruited to CHAIR promoter during heart failure to suppress its expression. Reciprocally, CHAIR interacted with DNMT3A to inhibit its DNA-binding activity. Taken together, our data revealed a new cardioprotective lncRNA that represses heart failure through an epigenetic mechanism.

Abstract 13171: Cellular Basis of Angiotensin-(1-7) Produced Augmentation on Left Ventricular Contractile Function in Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xiaowei Zhang ◽  
Heng-Jie Cheng ◽  
Peng Zhou ◽  
Tiankai Li ◽  
Wei-Min Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Enzyme Inhibitor ◽  
Contractile Function ◽  
Heart Diseases ◽  
Cardiovascular Effects ◽  
Fold Increase ◽  
Left Ventricular ◽  
Inotropic Effects ◽  
Cardiac Depression ◽  
Hoe 140

Background: Accumulating evidence suggests that Angiotensin (A)-(1-7) exhibits cardiovascular effects that are in opposition to that of AII, thus providing protection against heart diseases. However, the exact means by which A-(1-7) affords cardioprotection are unclear. Its direct cardiac effect is not well understood. We previously showed that in heart failure (HF), AII decreases left ventricle (LV) contractility. Whether A-(1-7) may antagonize AII-induced cardiac depression, thereby contributing to its beneficial actions in HF remains to be determined. We assessed the hypothesis that A-(1-7) may produce positive modulation on [Ca 2+ ] i regulation and LV and myocyte contraction via A-(1-7) receptors, coupled with nitric oxide (NO)/bradykinin (BK)-mediated mechanism. Methods: We measured LV contractility changes after A-(1-7) (650 ng/kg, iv), which produced a 20-fold increase in plasma A-(1-7) levels, mimicking the elevations caused by angiotensin-converting enzyme inhibitor therapy in HF, and compared myocyte contractile, [Ca 2+ ] i transient ([Ca 2+ ] iT ) and I Ca,L responses to A-(1-7) (10 -5 M) in 14 rats with isoproterenol induced HF (3 months after 170 mg/kg sq for 2 days). In the subsets of cell contractile study, myocytes were pretreated to inhibit NO synthase (L-NAME, 10 -5 M), BK (HOE 140, 10 -6 M) or A-(1-7) receptor [D-Ala 7 ]-A-(1-7), 10 -5 M) followed with A-(1-7) exposure. Results: Compared with baseline, after A-(1-7), E ES (47%, 1.0 vs 0.68 mmHg/μl) and M SW (49%, 94.3 vs 62.8 mmHg) were increased, indicating enhanced LV contractility. In HF myocytes, A-(1-7) increased myocyte percent shortening (28%, 6.8% vs 5.3%), the velocity of contraction (31%, 106.4 vs 74.5 μm/sec) and relengthening (41%, 74.7vs 50.1 μm/sec) accompanied by significantly-increased [Ca 2+ ] iT (27%, 0.19 vs 0.15 pA/pF) and I Ca,L (24%, 6.3 vs 5.1pA/pF). L-NAME increased, HOE 140 decreased, and A-(1-7) receptor blockade prevented myocyte contractile responses to A-(1-7). Conclusion: In HF, clinically-relevant concentrations of A-(1-7) counteracted AII-induced cardiac depression, increased [Ca 2+ ] iT and I Ca,L , and produced positive inotropic effects in both LV and myocytes. These effects are coupled with A-(1-7) receptors and involve activation of NO/BK pathways.

Prospects for the use of thyroid hormones in patients with heart failure

2021 ◽  
Author(s):  
S. M. Pyvоvar ◽  
Yu. S. Rudyk ◽  
О. B. Krоtоva ◽  
L. V. Panina
Keyword(s):  
Heart Failure ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Animal Studies ◽  
Cardiac Tissue ◽  
Contractile Function ◽  
Heart Function ◽  
Experimental Studies ◽  
Tissue Level ◽  
Free Triiodothyronine

Thyroid hormone therapy in the setting of heart failure is still an «open book» today. There are several unanswered questions: the regimen, doses and schedule of the use of thyroid hormones, the consequences of such therapy. At the same time, the presence of a comorbid pathology of the thyroid gland, which requires the appointment of levothyroxine, allows one to partially answer these questions. Thyroid hormones affect the diastolic and systolic functions of the myocardium. Ventricular contractile function is also affected by changes in hemodynamic conditions secondary to thyroid hormones and peripheral vascular tone. Thyroid hormone homeostasis maintains a positive ventricular-arterial ratio, resulting in a favorable balance for heart function. Experimental studies in rats have shown that chronic hypothyroidism alone can eventually lead to heart failure. Other studies suggest a decrease in the level of free triiodothyronine in the myocardium after myocardial infarction or with arterial hypertension due to the activation of type 3 deiodinase, which leads to deactivation of triiodothyronine and thyroxine. To address these issues, the researchers propose conducting multicenter, randomized, placebo-controlled trials to evaluate the effects of thyroxine replacement in patients with chronic heart failure. The review highlights the growing body of evidence from animal studies and small clinical trials that suggests that low thyroid activity at the cardiac tissue level can negatively affect the progression of heart failure and that treatment with thyroid hormones can lead to an improved prognosis.

Abstract 1247: Heart Function is Transiently Sustained Despite a Near Loss of SERCA2 Protein in Cardiomyocyte-specific Serca2 null Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kristin B Andersson ◽  
Alexandra V Finsen ◽  
Ivar Sjaastad ◽  
Yibin Wang ◽  
Ju Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Output ◽  
Diastolic Pressure ◽  
Heart Function ◽  
Clinical Signs ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Lung Weight ◽  
Adult Mice

The SERCA2 Ca 2+ ATPase is of central importance for refilling of the sarcoplasmic reticulum (SR) Ca 2+ store and cardiac contractility. Reduced SERCA2 function is associated with heart failure. We hypothesized that loss of SERCA2 would result in immediate severe myocardial contractile dysfunction and death. Transgenic mice were generated with a Cre-loxP strategy in which tamoxifen induces Serca2 ( Atp2a2 ) gene excision in the cardiomyocytes (SERCA2KO) of adult mice. In SERCA2KO mice, SERCA2 protein was rapidly reduced in left ventricular myocardium with a half-life < 3 days. After 4 weeks, SERCA2 protein was reduced to < 5% of control values. In isolated cardiomyocytes, SERCA2a, SERCA2b, SERCA1 and SERCA3 proteins were not detectable. Strikingly, SERCA2KO mice did not present clinical signs of circulatory failure at 4 weeks. Fractional shortening was preserved, and cardiac output was reduced to 80% of control values. The left atrial diameter, lung weight and left ventricular end-diastolic pressure (LVEDP) were slightly increased in SERCA2KO mice compared with controls, and the maximal rates of pressure development and decline in the left ventricle were affected with a prolongation of the ventricular relaxation time. After seven weeks, SERCA2KO mice developed severe congestive heart failure with dilated chambers, elevated LVEDP and pronounced increases in lung and atrial weights. Cardiac output was reduced to 70% of control values. There were no indications of major cardiomyocyte disarray in the myocardium at the 4 or 7 week timepoints. The abundance of Na + ,Ca 2+ exchanger, L-type Ca 2+ channel 1c and alpha2delta1 subunit proteins and Pmca1 mRNA were all increased at 4 and 7 weeks. The expression of calsequestrin protein and Ryr2 mRNA were unchanged. L-type Ca 2+ channel alpha2delta1 subunit and PMCA1 expression were further enhanced at 7 weeks in SERCA2KO mice. Thus, cardiac function is supported in SERCA2KO mice for several weeks despite the near absence of SERCA2 protein. Alterations in the expression of Ca 2+ transporting proteins suggest that Ca 2+ transients are generated over the plasma membrane rather than the SR. However, the adaptations induced by loss of SERCA2 are not sufficient for long-term support of heart function in adult mice.

scholarly journals Klotho Deficiency Causes Heart Aging via Impairing the Nrf2-GR Pathway

2020 ◽  
Author(s):  
Kai Chen ◽  
Shirley Wang ◽  
Qiwei Wilton Sun ◽  
Bo Zhang ◽  
Mujib Fnu Ullah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Therapeutic Strategy ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Large Population ◽  
Cardiac Aging ◽  
Heart Size ◽  
Old Mice ◽  
Fractional Shortening

Rationale: Cardiac aging is an important contributing factor for heart failure which affects a large population but remains poorly understood. Objective: The purpose of this study is to investigate whether Klotho plays a role in cardiac aging. Methods and Results: Heart function declined in old mice (24 months), as evidenced by decreases in fractional shortening, ejection fraction, and cardiac output. Heart size and weight, cardiomyocyte size and cardiac fibrosis were increased in old mice, indicating that aging causes cardiac hypertrophy and remodeling. Circulating Klotho levels were dramatically decreased in old mice, which prompted us to investigate whether the Klotho decline may cause heart aging. We found that Klotho gene mutation (KL-/-) largely decreased serum klotho levels and impaired heart function. Interestingly, supplement of exogenous secreted Klotho prevented heart failure, hypertrophy, and remodeling in both old mice and KL (-/-) mice. Secreted Klotho treatment inhibited excessive cardiac oxidative stress, senescence and apoptosis in old mice and KL (-/-) mice. Serum phosphate levels in KL (-/-) mice were kept in the normal range, suggesting that Klotho deficiency-induced heart aging is independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed glutathione reductase (GR) expression and activity in the heart via inhibition of transcription factor Nrf2. Furthermore, cardiac-specific overexpression of GR prevented excessive oxidative stress, apoptosis, and heart failure in both old and KL (-/-) mice. Conclusions: Klotho deficiency causes cardiac aging via impairing the Nrf2-GR pathway. Supplement of exogenous secreted Klotho represents a promising therapeutic strategy for aging-associated cardiomyopathy and heart failure.

Abstract 12606: Autophagy is Required for Mitochondrial Biogenesis in the Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Zhonggang Li ◽  
Quanjiang Zhang ◽  
Karla Pires ◽  
E. Dale Abel
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Contractile Function ◽  
Heart Function ◽  
Early Event ◽  
Acid Oxidation ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Deficient Mice

Autophagy is an essential process that maintains cellular homeostasis via lysosomal degradation pathways. Autophagy has been found to be involved in various pathophysiological conditions in the heart, including myocardial hypertrophy and ischemic heart disease. However, the precise mechanism by which autophagy maintains cardiac function in the non-stressed heart is incompletely understood. We generated cardiac-specific ATG3 deficient mice (cATG3 KO mice) by crossing αMHC-Cre mice with floxed ATG3 mice. Relative to their wild type (WT) littermates, cATG3 KO mice revealed reduced ATG3 expression and inhibited autophagy specifically in the heart. At 4 months of age, cATG3 KO mice showed impaired cardiac contractile function, characterized by a 25% reduction in fractional shortening by echocardiography (p <0.01), Moreover, cATG3 KO mice revealed increased lipid accumulation, reduced fatty acid oxidation and impaired mitochondrial respirations in the heart, without evidence of fibrosis or inflammation. Mitochondrial dysfunction in cATG3 KO mice was accompanied with mitochondrial content loss and reduced expression of mitochondrial biogenesis related genes (PGC1α, NRF1, NRF2 and TFAM). Interestingly, autophagy inhibition, induced mitochondrial biogenesis defects and mitochondrial dysfunction in neonatal cATG3 KO mice (1 week old), prior to the onset of cardiac contractile dysfunction and heart failure, suggesting that cardiac mitochondrial dysfunction may be an early event in the progression of heart failure in the autophagy deficient mice. Finally, in response to exercise training mitochondrial biogenesis (PGC1 alpha induction and increased respiration rates) was completely inhibited in ATG3 deficient mice. In conclusion, autophagy is essential for generating signals that promote mitochondrial biogenesis, and is indispensable for normal heart function under basal conditions.

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