Diabetic pregnancy as a novel risk factor for cardiac dysfunction in the offspring—the heart as a target for fetal programming in rats

Abstract Aims/hypothesis The impact of diabetic pregnancy has been investigated extensively regarding offspring metabolism; however, little is known about the influence on the heart. We aimed to characterise the effects of a diabetic pregnancy on male adult offspring cardiac health after feeding a high-fat diet in an established transgenic rat model. Methods We applied our rat model for maternal type 2 diabetes characterised by maternal insulin resistance with hyperglycaemia and hyperinsulinaemia. Diabetes was induced preconceptionally via doxycycline-induced knock down of the insulin receptor in transgenic rats. Male wild-type offspring of diabetic and normoglycaemic pregnancies were raised by foster mothers, followed up into adulthood and subgroups were challenged by a high-fat diet. Cardiac phenotype was assessed by innovative speckle tracking echocardiography, circulating factors, immunohistochemistry and gene expression in the heart. Results When feeding normal chow, we did not observe differences in cardiac function, gene expression and plasma brain natriuretic peptide between adult diabetic or normoglycaemic offspring. Interestingly, when being fed a high-fat diet, adult offspring of diabetic pregnancy demonstrated decreased global longitudinal (−14.82 ± 0.59 vs −16.60 ± 0.48%) and circumferential strain (−23.40 ± 0.57 vs −26.74 ± 0.34%), increased relative wall thickness (0.53 ± 0.06 vs 0.37 ± 0.02), altered cardiac gene expression, enlarged cardiomyocytes (106.60 ± 4.14 vs 87.94 ± 1.67 μm), an accumulation of immune cells in the heart (10.27 ± 0.30 vs 6.48 ± 0.48 per fov) and higher plasma brain natriuretic peptide levels (0.50 ± 0.12 vs 0.12 ± 0.03 ng/ml) compared with normoglycaemic offspring on a high-fat diet. Blood pressure, urinary albumin, blood glucose and body weight were unaltered between groups on a high-fat diet. Conclusions/interpretation Diabetic pregnancy in rats induces cardiac dysfunction, left ventricular hypertrophy and altered proinflammatory status in adult offspring only after a high-fat diet. A diabetic pregnancy itself was not sufficient to impair myocardial function and gene expression in male offspring later in life. This suggests that a postnatal high-fat diet is important for the development of cardiac dysfunction in rat offspring after diabetic pregnancy. Our data provide evidence that a diabetic pregnancy is a novel cardiac risk factor that becomes relevant when other challenges, such as a high-fat diet, are present. Graphical abstract

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Cardiac Hypertrophy and Brain Natriuretic Peptide Levels in an Ovariectomized Rat Model Fed a High-Fat Diet

Medical Science Monitor Basic Research ◽

10.12659/msmbr.907162 ◽

2017 ◽

Vol 23 ◽

pp. 380-391 ◽

Cited By ~ 3

Author(s):

Gleisy Kelly Goncalves ◽

Thiago Henrique Caldeira de Oliveira ◽

Najara de Oliveira Belo

Keyword(s):

Cardiac Hypertrophy ◽

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Rat Model ◽

High Fat Diet ◽

Ovariectomized Rat ◽

High Fat

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Resveratrol Supplementation Attenuates Cognitive and Molecular Alterations Under Maternal High-Fat Diet Intake: Multigenerational Epigenetic Inheritance.

10.20944/preprints202012.0115.v1 ◽

2020 ◽

Author(s):

Vanesa Izquierdo ◽

Verónica Palomera-Ávalos ◽

Mercè Pallàs ◽

Christian Griñán-Ferré

Keyword(s):

Gene Expression ◽

Cognitive Decline ◽

High Fat Diet ◽

Epigenetic Inheritance ◽

Adult Offspring ◽

High Fat ◽

Molecular Alterations ◽

Protein Levels ◽

Age Related ◽

Inflammatory Profile

Environmental factors as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. The epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol HFD+RV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RV groups and their offspring. Molecularly, a significant increase in 5-mC levels, as well as increased gene expression of Dnmt1 and Dnmt3a in HFD+RV F1 group, were found. Furthermore, a significantly increased of m6A levels in HFD+RV F1 were found, and there were changes in gene expression of its enzymes (Mettl3 and Fto). Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as Il1-β, Il-6, Tnf-α, Cxcl-10, Mcp-1 and Tgf-β1 in HFD+RV and HFD+RV F1 groups. Moreover, there was increased gene expression of neurotrophins such as Ngf and Nt3 and its receptors TrkA and TrkB. Likewise, an increase in protein levels of BDNF and p-Akt in HFD+RV F1 was found. These results suggest that maternal RV supplementation under HFD intake prevents cognitive decline in SAMP8 adult offspring, promoting a reduction in triglycerides and leptin plasma levels, changes in the pro-inflammatory profile, restoring the epigenetic landscape as well as synaptic plasticity.

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A Maternal High Fat Diet Leads to Sex-Specific Programming of Mechanical Properties in Supraspinatus Tendons of Adult Rat Offspring

Frontiers in Nutrition ◽

10.3389/fnut.2021.729427 ◽

2021 ◽

Vol 8 ◽

Author(s):

Scott M. Bolam ◽

Vidit V. Satokar ◽

Subhajit Konar ◽

Brendan Coleman ◽

Andrew Paul Monk ◽

...

Keyword(s):

Gene Expression ◽

High Fat Diet ◽

Maternal Diet ◽

Biomechanical Properties ◽

Female Offspring ◽

Male Offspring ◽

Chow Diet ◽

Adult Offspring ◽

High Fat ◽

The Impact

Background: Over half of women of reproductive age are now overweight or obese. The impact of maternal high-fat diet (HFD) is emerging as an important factor in the development and health of musculoskeletal tissues in offspring, however there is a paucity of evidence examining its effects on tendon. Alterations in the early life environment during critical periods of tendon growth therefore have the potential to influence tendon health that cross the lifespan. We hypothesised that a maternal HFD would alter biomechanical, morphological and gene expression profiles of adult offspring rotator cuff tendon.Materials and Methods: Female Sprague-Dawley rats were randomly assigned to either: control diet (CD; 10% kcal or 43 mg/g from fat) or HFD (45% kcal or 235 mg/g from fat) 14 days prior to mating and throughout pregnancy and lactation. Eight female and male offspring from each maternal diet group were weaned onto a standard chow diet and then culled at postnatal day 100 for tissue collection. Supraspinatus tendons were used for mechanical testing and histological assessment (cellularity, fibre organisation, nuclei shape) and tail tendons were collected for gene expression analysis.Results: A maternal HFD increased the elasticity (Young's Modulus) in the supraspinatus tendon of male offspring. Female offspring tendon biomechanical properties were not affected by maternal HFD. Gene expression of SCX and COL1A1 were reduced in male and female offspring of maternal HFD, respectively. Despite this, tendon histological organisation were similar between maternal diet groups in both sexes.Conclusion: An obesogenic diet during pregnancy increased tendon elasticity in male, but not female, offspring. This is the first study to demonstrate that maternal diet can modulate the biomechanical properties of offspring tendon. A maternal HFD may be an important factor in regulating adult offspring tendon homeostasis that may predispose offspring to developing tendinopathies and adverse tendon outcomes in later life.

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Angiotensin Receptor Blocker and Neprilysin Inhibitor Suppresses Cardiac Dysfunction by Accelerating Myocardial Angiogenesis in Apolipoprotein E-Knockout Mice Fed a High-Fat Diet

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1155/2021/9916789 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Yasunori Suematsu ◽

Kohei Tashiro ◽

Hidetaka Morita ◽

Akihito Ideishi ◽

Takashi Kuwano ◽

...

Keyword(s):

Apolipoprotein E ◽

Natriuretic Peptide ◽

Knockout Mice ◽

Cardiac Dysfunction ◽

High Fat Diet ◽

Angiotensin Receptor Blocker ◽

Left Ventricular ◽

Angiotensin Receptor ◽

High Fat ◽

Apolipoprotein E Knockout Mice

Hypothesis. Myocardial angiogenesis is important for maintaining cardiac contractile function in patients with cardiac hypertrophy. Evidence shows that angiotensin receptor blocker and neprilysin inhibitors (ARNIs) improve heart failure. The present study investigated the myocardial angiogenic effect of valsartan plus sacubitril in early-stage cardiac dysfunction. Materials and Methods. Male apolipoprotein E-knockout mice fed a high-fat diet were divided into control (CTL), valsartan (30 mg/kg) (VAL), sacubitril (30 mg/kg) (SAC), and valsartan plus sacubitril (30 mg/kg each) (VAL/SAC) groups after 4 weeks of prefeeding and were subsequently treated for 12 weeks. Results. The VAL/SAC group exhibited significantly higher serum brain natriuretic peptide levels; more subtle changes in left ventricular systolic diameter, fractional shortening, and ejection fraction, and significantly higher expression levels of natriuretic peptide precursor B and markers of angiogenesis, including clusters of differentiation 34, vascular endothelial growth factor A, and monocyte chemotactic protein 1, than the CTL group. Conclusions. Valsartan plus sacubitril preserved left ventricular systolic function in apolipoprotein E-knockout mice fed a high-fat diet. This result suggests that myocardial angiogenic factors induced by ARNI might provide cardioprotective effects.

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Neutrophil microvesicles drive atherosclerosis by deliveringmiR-155to atheroprone endothelium

10.1101/319392 ◽

2018 ◽

Cited By ~ 3

Author(s):

Ingrid Gomez ◽

Ben Ward ◽

Celine Souilhol ◽

Chiara Recarti ◽

Mark Ariaans ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Risk Factor ◽

High Fat Diet ◽

Vascular Inflammation ◽

Atherosclerotic Plaques ◽

High Fat ◽

Complex Flow ◽

Inflammatory Gene Expression ◽

Disturbed Flow

AbstractNeutrophils have been implicated in the pathogenesis of atherosclerosis, a lipid-driven disease of arteries, but they are seldom found in atherosclerotic plaques. To resolve this longstanding paradox, we investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Clinical and pre-clinical studies revealed that levels of circulating neutrophil microvesicles were enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulated at disease-prone regions of arteries that are exposed to complex flow patterns, and they promoted vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, it was demonstrated that neutrophil microvesicles promoted inflammatory gene expression by delivering a microRNA (miR-155) that enhanced NF-κB activation. Similary, neutrophil microvesicles increased miR-155 and enhanced NF-κB at disease-prone sites of disturbed flow in arteries of mice. We conclude that delivery of microvesicles carrying miR-155 to disease-prone regions of arteries provides a novel mechanism by which neutrophils contribute to vascular inflammation and atherogenesis.

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Resveratrol Supplementation Attenuates Cognitive and Molecular Alterations under Maternal High-Fat Diet Intake: Epigenetic Inheritance over Generations

International Journal of Molecular Sciences ◽

10.3390/ijms22031453 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1453

Author(s):

Vanesa Izquierdo ◽

Verónica Palomera-Ávalos ◽

Mercè Pallàs ◽

Christian Griñán-Ferré

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Cognitive Decline ◽

High Fat Diet ◽

Dna Methyltransferase ◽

Inflammatory Factors ◽

Adult Offspring ◽

High Fat ◽

Monocyte Chemoattractant Protein 1 ◽

Age Related

Environmental factors such as maternal high-fat diet (HFD) intake can increase the risk of age-related cognitive decline in adult offspring. Epigenetic mechanisms are a possible link between diet effect and neurodegeneration across generations. Here, we found a significant decrease in triglyceride levels in a high-fat diet with resveratrol (RSV) HFD + RSV group and the offspring. Firstly, we obtained better cognitive performance in HFD+RSV groups and their offspring. Molecularly, a significant increase in DNA methylation (5-mC) levels, as well as increased gene expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a in HFD + RSV F1 group, were found. Furthermore, a significant increase of N6-Methyladenosine methylation (m6A) levels in HFD+RSV F1, as well as changes in gene expression of its enzymes Methyltransferase like 3 (Mettl3) and FTO alpha-ketoglutarate dependent dioxygenase (Fto) were found. Moreover, we found a decrease in gene expression levels of pro-inflammatory markers such as Interleukin 1β (Il1-β), Interleukin 6 (Il-6), Tumor necrosis factor-α (Tnf-α), C-X-C motifchemokine ligand 10 (Cxcl-10), the pro-inflammatory factors monocyte chemoattractant protein 1 (Mcp-1) and Tumor growth factor-β1 (Tgf-β1) in HFD+RSV and HFD+RSV F1 groups. Moreover, there was increased gene expression of neurotrophins such as Neural growth factor (Ngf), Neurotrophin-3 (Nt3), and its receptors Tropomyosin receptor kinase TrkA and TrkB. Likewise, an increase in protein levels of brain-derived neurotrophic factor (BDNF) and phospho-protein kinase B (p-Akt) in HFD+RSV F1 was found. These results suggest that maternal RSV supplementation under HFD intake prevents cognitive decline in senescence-accelerated mice prone 8 (SAMP8) adult offspring, promoting a reduction in triglycerides and leptin plasma levels, changes in the pro-inflammatory profile, and restoring the epigenetic landscape as well as synaptic plasticity.

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