IGF-IR signaling attenuates the age-related decline of diastolic cardiac function

Insulin-like growth factor (IGF-I) signaling has been implicated to play an important role in regulation of cardiac growth, hypertrophy, and contractile function and has been linked to the development of age-related congestive heart failure. Here, we address the question to what extent cardiomyocyte-specific IGF-I signaling is essential for maintenance of the structural and functional integrity of the adult murine heart. To investigate the effects of IGF-I signaling in the adult heart without confounding effects due to IGF-I overexpression or adaptation during embryonic and early postnatal development, we inactivated the IGF-I receptor (IGF-IR) by a 4-hydroxytamoxifen-inducible Cre recombinase in adult cardiac myocytes. Efficient inactivation of the IGF-IR (iCMIGF-IRKO) as assessed by Western analysis and real-time PCR went along with reduced IGF-I-dependent Akt and GSK3β phosphorylation. Functional analysis by conductance manometry and MRI revealed no functional alterations in young adult iCMIGF-IRKO mice (age 3 mo). However, when induced in aging mice (11 mo) diastolic cardiac function was depressed. To address the question whether insulin signaling might compensate for the defective IGF-IR signaling, we inactivated β-cells by streptozotocin. However, the diabetes-associated functional depression was similar in control and iCMIGF-IRKO mice. Similarly, analysis of the cardiac gene expression profile on 44K microarrays did not reveal activation of overt adaptive processes. Endogenous IGF-IR signaling is required for conservation of cardiac function of the aging heart, but not for the integrity of cardiac structure and function of young hearts.

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Abstract 247: Scaffold-stiffness Dependent Notch1 Activation Regulates Cardiogenic Gene Expression In Cardiac Progenitor Cells

Circulation Research ◽

10.1161/res.113.suppl_1.a247 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Archana V Boopathy ◽

Pao L Che ◽

Yoshie Narui ◽

Khalid Salaita ◽

Michael E Davis

Keyword(s):

Gene Expression ◽

Smooth Muscle ◽

Cardiac Function ◽

Progenitor Cells ◽

Adult Stem Cells ◽

Cardiac Progenitor Cells ◽

Critical Pathway ◽

Cardiac Gene Expression ◽

Self Assembling ◽

Cardiac Gene

Rationale: Cardiac progenitor cells (CPCs) are multipotent, self-renewing cells that can regenerate the myocardium and improve cardiac function in animal models of myocardial infarction (MI). However, limited survival of stem/progenitor cells inhibits cardiac regeneration. Force dependent Notch activation promotes cardiac development and cardiac gene expression in many adult stem cells. As dysregulation of Notch signaling leads to embryonic lethal cardiovascular defects, activating this critical pathway during cell transplantation could improve efficacy of stem cell therapy. Objective: Investigate i) whether self-assembling peptide scaffolds can be used to activate Notch1 signaling in CPCs to promote cardiogenic differentiation and ii) the effect of scaffold stiffness on Notch1 activation and differentiation. Methods: Rat CPCs (c-kit + ) were cultured for 48h in 3D self-assembling scaffolds of varying stiffness (1% low, 2% high): empty scaffolds (RADA), scaffolds modified with peptide mimicking Notch1 ligand, Jagged1 (RJAG), or scaffolds modified with a scrambled peptide (RSCR) and cardiogenic gene expression measured by qRT-PCR. CHO cells expressing Notch1 responsive YFP were also cultured in the above scaffolds for 48h and YFP expression was determined. Results are mean ± SEM with p<0.05 considered significant by one or two-way ANOVA with appropriate post test. Results: In the Notch1 reporter cells, Notch1 activation increased significantly in presence of RJAG (p<0.01) and on increasing scaffold stiffness (p<0.01,n=6) indicating scaffold stiffness-dependent Notch1 activation. Culture of CPCs in RJAG containing 1% scaffolds (low stiffness) significantly increased early endothelial and smooth muscle but not cardiac gene expression while in 2% scaffolds (high stiffness) significantly increased only cardiac and not endothelial or smooth muscle gene expression (p<0.05, n≥4). Conclusions: Taken together, these data show that i) Notch1 activation in 3D is dependent on ligand density and scaffold stiffness and ii) stiffness dependent Notch1 activation differentially regulates cardiogenic gene expression in CPCs. Therefore, delivery of CPCs in JAG containing scaffolds could be used to improve cardiac function following MI.

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Chronic β-agonist administration affects cardiac function of adult but not old rats, independent of β-adrenoceptor density

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01254.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. H344-H349 ◽

Cited By ~ 22

Author(s):

Paul Gregorevic ◽

James G. Ryall ◽

David R. Plant ◽

Martin N. Sillence ◽

Gordon S. Lynch

Keyword(s):

Cardiac Function ◽

Contractile Function ◽

Heart Function ◽

Relative Increase ◽

Left Ventricular ◽

Aged Rats ◽

Adult Rats ◽

Age Related ◽

Heart Mass

Although β-adrenoceptor agonists have clinical merit for attenuating the age-related loss of skeletal muscle mass and strength (sarcopenia), potential cardiac-related side effects may limit their clinical application. The aim of this study was to determine whether chronic β-agonist administration impairs cardiac function in adult or aged rats. Adult (16 mo) and aged (28 mo) Fischer 344 rats were treated with fenoterol (1.4 mg·kg−1·day−1 ip) or vehicle for 4 wk. Heart function was assessed in vitro before analyses of cardiac structure and β-adrenoceptor density. Heart mass increased 17% and 25% in fenoterol-treated adult and aged rats, respectively. The increased heart mass in aged, but not adult, rats was associated with a relative increase in collagen content. Cardiac hypertrophy in adult rats was associated with an increase in left ventricular developed pressure, a marked reduction in cardiac output, and a reduction in coronary flow per unit heart mass. In contrast, negligible differences in ventricular function were observed in fenoterol-treated aged rats. The differential effect on contractile function was not associated with age-related differences in β-adrenoceptor density but, rather, an age-related increase in downregulation after treatment. Our results show that chronic β-agonist treatment impairs cardiac function to a greater extent in adult than in aged rats. These results provide important information regarding the potential effects of chronic β-agonist use on cardiac function and the future development of safe and effective treatments for sarcopenia.

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Hypoxic pHi and function modulation by Na+/H+ exchange and alpha-adrenoreceptor inhibition in heart in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.6.h2664 ◽

1997 ◽

Vol 272 (6) ◽

pp. H2664-H2670 ◽

Cited By ~ 3

Author(s):

M. A. Portman ◽

Y. Xiao ◽

B. G. Broers ◽

X. H. Ning

Keyword(s):

Cardiac Function ◽

Contractile Function ◽

High Energy ◽

Left Ventricular ◽

Resonance Spectroscopy ◽

Cardiac Contractile Function ◽

Significant Drop ◽

And Function ◽

Phi Regulation

Regulation of intracellular pH (pHi) may contribute to maintenance of cardiac contractile function during graded hypoxia in vivo. To test this hypothesis, we disturbed pHi regulation in vivo using two approaches: alpha-adrenoreceptor antagonism with phentolamine (1 mg/kg) (Phen; n = 9); and Na+/H+ exchange inhibition with HOE-642 (2 mg/kg; n = 6) before graded hypoxia in open-chest sheep. Hemodynamic parameters including left ventricular maximal pressure development (dP/dtmax) cardiac index (CI), and left ventricular power were monitored continuously and simultaneously with high-energy phosphate levels and pHi, measured with 31P nuclear magnetic resonance spectroscopy in Phen, HOE-642, and control (Con; n = 9). In subgroups (n = 6) in Con and Phen, coronary flow, myocardial oxygen consumption (MVO2), and lactate uptake were also measured. During hypoxia, the functional parameters left ventricular dP/dtmax, CI, and left ventricular power decreased significantly compared with baseline and Con values. These decreases were preceded by a significant drop (P < 0.05) in pHi from 7.10 +/- 0.04 to 6.69 +/- 0.05 in Phen and corresponded temporally to a pHi drop from 7.10 +/- 0.02 to 6.77 +/- 0.03 in HOE-642. Decreases in pHi in Phen were not preceded by decreases in cardiac function or MVO2. In contrast, cardiac function parameters increased significantly in Con, whereas no significant pHi decrease occurred (7.07 +/- 0.03 to 6.98 +/- 0.04). We conclude that these data indicate that pHi regulation can be disrupted through alpha-adrenergic antagonism or Na+/H(+)-exchange inhibition in vivo. These studies demonstrate that pHi regulation performs a role in the modulation of cardiac function during hypoxia in vivo.

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III. Senescent enteric nervous system: lessons from extraintestinal sites and nonmammalian species

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00224.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. G1020-G1026 ◽

Cited By ~ 28

Author(s):

John W. Wiley

Keyword(s):

Life Span ◽

Cellular Function ◽

Colonic Transit ◽

Advanced Age ◽

Physiological Aging ◽

Functional Changes ◽

Age Related ◽

Igf I ◽

And Function ◽

Kinase Expression

Functional changes in GI motility associated with advanced age include slowing of gastric emptying, decreased peristalsis, and slowing of colonic transit. These changes appear to be associated with region-specific loss of neurons and impaired function. The mechanism(s) underlying physiological aging are likely to be multifactorial. Alterations in specific signal transduction pathways have been reported at the level of the receptor and postreceptor events including kinase expression and function, mitochondrial function, and activation of the apoptosis cascade. Advanced age is associated with increased oxidative stress and its concomitant effects on cellular function. Whereas no specific genes have been causally linked to life span in mammals, studies involving nonmammalian species suggest that specific genes are involved in determining life span and age-related changes in cellular function. Caloric restriction is the only intervention shown to slow aging in a variety of species. Recent studies implicate a possible role for an insulin/IGF-I cascade in the region- and tissue-specific changes associated with physiological aging.

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Differential effects of REV-ERBα/β agonism on cardiac gene expression, metabolism, and contractile function in a mouse model of circadian disruption

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00709.2019 ◽

2020 ◽

Vol 318 (6) ◽

pp. H1487-H1508 ◽

Cited By ~ 3

Author(s):

Sobuj Mia ◽

Mariame S. Kane ◽

Mary N. Latimer ◽

Cristine J. Reitz ◽

Ravi Sonkar ◽

...

Keyword(s):

Gene Expression ◽

Mouse Model ◽

Mitochondrial Function ◽

Contractile Function ◽

Interstitial Fibrosis ◽

Glycogen Synthesis ◽

Circadian Clocks ◽

Cardiac Gene Expression ◽

Transcriptional Modulators ◽

Cardiac Gene

Circadian clocks are composed of more than 10 interconnected transcriptional modulators, all of which have the potential to influence the cardiac transcriptome (and ultimately cardiac processes). Previous studies indicate that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit a dysfunctional circadian clock (including decreased REV-ERBα/β expression) in the heart, associated with abnormalities in cardiac mitochondrial function, metabolism, signaling, and contractile function. Here we highlight decreased REV-ERBα/β as a mediator of glycogen synthesis, cardiomyocyte size, interstitial fibrosis, and contractile function abnormalities observed in CBK hearts.

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Calcium handling precedes cardiac differentiation to initiate the first heartbeat

eLife ◽

10.7554/elife.17113 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 30

Author(s):

Richard CV Tyser ◽

Antonio MA Miranda ◽

Chiann-mun Chen ◽

Sean M Davidson ◽

Shankar Srinivas ◽

...

Keyword(s):

Gene Expression ◽

Contractile Function ◽

Rapid Development ◽

Mouse Embryos ◽

Cardiac Differentiation ◽

Calcium Handling ◽

Heart Tube ◽

Cardiac Gene Expression ◽

Stage Of Development ◽

Cardiac Gene

The mammalian heartbeat is thought to begin just prior to the linear heart tube stage of development. How the initial contractions are established and the downstream consequences of the earliest contractile function on cardiac differentiation and morphogenesis have not been described. Using high-resolution live imaging of mouse embryos, we observed randomly distributed spontaneous asynchronous Ca2+-oscillations (SACOs) in the forming cardiac crescent (stage E7.75) prior to overt beating. Nascent contraction initiated at around E8.0 and was associated with sarcomeric assembly and rapid Ca2+ transients, underpinned by sequential expression of the Na+-Ca2+ exchanger (NCX1) and L-type Ca2+ channel (LTCC). Pharmacological inhibition of NCX1 and LTCC revealed rapid development of Ca2+ handling in the early heart and an essential early role for NCX1 in establishing SACOs through to the initiation of beating. NCX1 blockade impacted on CaMKII signalling to down-regulate cardiac gene expression, leading to impaired differentiation and failed crescent maturation.

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Role of NRSF/REST in the Regulation of Cardiac Gene Expression and Function

Circulation Journal ◽

10.1253/circj.cj-13-1210 ◽

2013 ◽

Vol 77 (11) ◽

pp. 2682-2686 ◽

Cited By ~ 15

Author(s):

Koichiro Kuwahara

Keyword(s):

Gene Expression ◽

Cardiac Gene Expression ◽

Cardiac Gene ◽

And Function

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SLMAP3 isoform modulates cardiac gene expression and function

PLoS ONE ◽

10.1371/journal.pone.0214669 ◽

2019 ◽

Vol 14 (4) ◽

pp. e0214669 ◽

Cited By ~ 3

Author(s):

Jana Mlynarova ◽

Mayra Trentin-Sonoda ◽

Fernanda Gaisler da Silva ◽

Jennifer L. Major ◽

Maysoon Salih ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Gene Expression ◽

Cardiac Gene ◽

And Function

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Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22137002 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7002

Author(s):

Marcus Negron ◽

Jeffrey Kristensen ◽

Van Thuan Nguyen ◽

Lauren E. Gansereit ◽

Frank J. Raucci ◽

...

Keyword(s):

Cardiac Function ◽

Interferon Γ ◽

Gene Encoding ◽

Growth And Survival ◽

Cardiometabolic Disorders ◽

Cardiac Gene ◽

Inflammatory Profile ◽

Underlying Mechanisms ◽

And Function ◽

Female Specific

Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

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