Female Rat Hearts Research Articles

Sub chronic Toxicity of Pregabalin and Possible Fibrotic Changes in Ovaries, Kidneys, Heart, and Lungs of Female Rats

Sub chronic Toxicity of Pregabalin and Possible Fibrotic Changes in Ovaries, Kidneys, Heart, and Lungs of Female Rats

Limosilactobacillus fermentum Strains with Claimed Probiotic Properties Exert Anti-oxidant and Anti-inflammatory Properties and Prevent Cardiometabolic Disorder in Female Rats Fed a High-Fat Diet.

This study assessed the effects of a mixed formulation containing Limosilactobacillus (L.) fermentum 139, L. fermentum 263, and L. fermentum 296 on cardiometabolic parameters, inflammatory markers, short-chain fatty acid (SCFA) fecal contents, and oxidative stress in colon, liver, heart, and kidney tissues of female rats fed a high-fat diet (HFD). Female Wistar rats were allocated into control diet (CTL, n = 6), HFD (n = 6), and HFD receiving L. fermentum formulation (HFD-LF, n = 6). L. fermentum formulation (1 × 109CFU/mL of each strain) was administered two twice a day for 4weeks. Administration of L. fermentum increased acetate and succinate fecal contents and reduced hyperlipidemia and hyperglycemia in rats fed a HFD (p < 0.05). Administration of L. fermentum decreased low-grade inflammation and improved antioxidant capacity along the gut, liver, heart, and kidney tissues in female rats fed a HFD (p < 0.05). Administration of L. fermentum prevented dyslipidemia, inflammation, and oxidative stress in colon, liver, heart, and kidney in female rats fed a HFD.

Inhibition of dipeptidyl peptidase-4 averts free fatty acids deposition in the hearts of oral estrogen-progestin contraceptive-induced hyperinsulinemic female rats.

Free fatty acid (FFA) deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which feature hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen-progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue, and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac FFA deposition in estrogen-progestin-treated female rats. From our data, estrogen-progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, TG/high-density lipoprotein cholesterol (TG/HDL-C) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway (ADA/XO/UA), lipid peroxidation, glycogen synthase activity, and alanine phosphatase; whereas cardiac glucose-6-phosphate dehydrogenase, Na+/K+-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG, TG/HDL-C ratio, and alkaline phosphatase. These were accompanied by reduced ADA/XO/UA pathway, lipid peroxidation, and augmented NO and Na+/K+-ATPase in estrogen-progestin OC-treated rats. DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen-progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders.

Pharmacokinetics and Tissue Distribution of Combined Triptolide and Paeoniflorin Regimen for Percutaneous Administration in Rats Assessed by Liquid Chromatography-Tandem Mass Spectrometry.

Triptolide (TP) has shown potential in rheumatoid arthritis (RA) treatment, but the narrow therapeutic window limits its clinical application. In clinical practice, the compatibility of Tripterygium wilfordii and Paeonia lactiflora is often used to attenuate the toxicity of TP, but its compatibility mechanism has not been fully elucidated. The aim of this study was to investigate the pharmacokinetics and tissue distribution of a combined regimen of TP and paeoniflorin (PF) after transdermal administration in male and female Sprague Dawley (SD) rats via a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The results showed that after percutaneous administration of TP and PF, there was no significant difference in AUC (0-t) (area under the curve) of TP, the peak concentration decreased by 58.17%, and the peak time was delayed. The AUC (0-t) of PF increased significantly (P < 0.01), the peak-reaching concentration and AUC (0-∞) increased, and the half-life and average retention time were shortened, indicating that TP absorption in rats may be delayed. After percutaneous administration of TP and PF, the content of TP in the heart, liver, spleen, lungs, and kidneys of male rats significantly decreased at 2 h (P < 0.05) and the drug concentration in the liver tissues significantly decreased at 2 h, 4 h, and 8 h (P < 0.05). The TP content in the spleen of female rats significantly decreased at 2 h and 4 h (P < 0.05) and also decreased in other tissues, but not significantly. After percutaneous administration of TP and PF, the PF content in the heart, liver, spleen, lungs, and kidneys of male and female rats had no significant difference. However, after percutaneous administration of TP and PF, the TP concentration in the skin increased, suggesting that the amount of TP retained in the skin increased, thereby reducing its content in blood and tissues, producing a reduction in toxicity effect.

3D single cell scale anatomical map of sex-dependent variability of the rat intrinsic cardiac nervous system

SummaryWe developed and analyzed a single cell scale anatomical map of the rat intrinsic cardiac nervous system (ICNS) across four male and three female hearts. We find the ICNS has a reliable structural organizational plan across individuals that provide the foundation for further analyses of the ICNS in cardiac function and disease. The distribution of the ICNS was evaluated by 3D visualization and data-driven clustering. The pattern, distribution, and clustering of ICNS neurons across all male and female rat hearts is highly conserved, demonstrating a coherent organizational plan where distinct clusters of neurons are consistently localized. Female hearts had fewer neurons, lower packing density, and slightly reduced distribution, but with identical localization. We registered the anatomical data from each heart to a geometric scaffold, normalizing their 3D coordinates for standardization of common anatomical planes and providing a path where multiple experimental results and data types can be integrated and compared.

Sex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis.

Increasing evidence suggests male sex as a potential risk factor for a higher incidence of cardiac fibrosis, stronger cardiac inflammation, and dilated cardiomyopathy (DCM) in human myocarditis. Chronic activation of the immune response in myocarditis may trigger autoimmunity. The experimental autoimmune myocarditis (EAM) model has been well established for the study of autoimmune myocarditis, however the role of sex in this pathology has not been fully explored. In this study, we investigated sex differences in the inflammatory response in the EAM model. We analyzed the cardiac function, as well as the inflammatory stage and fibrosis formation in the heart of EAM male and female rats. 21 days after induction of EAM, male EAM rats showed a decreased ejection fraction, stroke volume and cardiac output, while females did not. A significantly elevated number of infiltrates was detected in myocardium in both sexes, indicating the activation of macrophages following EAM induction. The level of anti-inflammatory macrophages (CD68+ ArgI+) was only significantly increased in female hearts. The expression of Col3A1 and fibrosis formation were more prominent in males. Furthermore, prominent pro-inflammatory factors were increased only in male rats. These findings indicate sex-specific alterations in the inflammatory stage of EAM, with a pro-inflammatory phenotype appearing in males and an anti-inflammatory phenotype in females, which both significantly affect cardiac function in autoimmune myocarditis.

Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β-Adrenergic Stimulation.

BackgroundBiological sex is an important modifier of cardiovascular disease and women generally have better outcomes compared with men. However, the contribution of cardiac fibroblasts (CFs) to this sexual dimorphism is relatively unexplored.Methods and ResultsIsoproterenol (ISO) was administered to rats as a model for chronic β‐adrenergic receptor (β‐AR)‐mediated cardiovascular disease. ISO‐treated males had higher mortality than females and also developed fibrosis whereas females did not. Gonadectomy did not abrogate this sex difference. To determine the cellular contribution to this phenotype, CFs were studied. CFs from both sexes had increased proliferation in vivo in response to ISO, but CFs from female hearts proliferated more than male cells. In addition, male CFs were significantly more activated to myofibroblasts by ISO. To investigate potential regulatory mechanisms for the sexually dimorphic fibrotic response, β‐AR mRNA and PKA (protein kinase A) activity were measured. In response to ISO treatment, male CFs increased expression of β1‐ and β2‐ARs, whereas expression of both receptors decreased in female CFs. Moreover, ISO‐treated male CFs had higher PKA activity relative to vehicle controls, whereas ISO did not activate PKA in female CFs.ConclusionsChronic in vivo β‐AR stimulation causes fibrosis in male but not female rat hearts. Male CFs are more activated than female CFs, consistent with elevated fibrosis in male rat hearts and may be caused by higher β‐AR expression and PKA activation in male CFs. Taken together, our data suggest that CFs play a substantial role in mediating sex differences observed after cardiac injury.

In vivo and ex vivo longitudinal follow-up of resveratrol supplementation or restauration of a normal diet in female rat hearts submitted to high-fat-high-sucrose diet

Prediabetic women are at greater risk of cardiovascular diseases than men, investigating new sex dependent strategic therapies is then essential to limit cardiovascular complications in prediabetic women. We aimed to evaluate the effects of resveratrol supplementation (RSV) or restauration of a standard diet on the heart of prediabetic female rats submitted to high-fat-high-sucrose diet (HFS). Wistar female rats were divided in 4 groups fed for 5 months with: normal or HFS diet (CTRL/HFS), HFS with RSV (1 mg/kg/day) during the last 2 months or HFS for 3 months and 2 months of standard diet (RSD). We performed a longitudinal in vivo study of cardiac function, morphology and perfusion by MRI, then rats underwent an IPGTT. Ex vivo experiments on isolated perfused hearts were realized to study cardiac function [rate pressure product (RPP), end diastolic pressure (EDP)] and energy metabolism with 31 P magnetic resonance spectroscopy during an ischemia-reperfusion injury (IR). Tissues were collected for analyzes. Five months of HFS diet-induced glucose intolerance ( P < 0.05), increased heart perfusion and heart/tibia length ratio (HTLR) ( P < 0.01 vs. CTRL). HFS also induced altered myocardial tolerance to IR, characterized by impaired RPP and EDP ( P < 0.001) associated with lower ATP and PCr levels during reperfusion ( P < 0.001, P < 0.05 vs. CTRL). RSV had no effect on glucose tolerance and heart perfusion ( P < 0.01 vs. CTRL) but normalized HTLR to CTRL level. Interestingly, RSV diminished EDP during reperfusion ( P < 0.05 vs. HFS). RSD normalized glucose tolerance without effect on heart perfusion and HTLR ( P < 0.01 and P < 0.05 vs. CTRL). RSD improved tolerance to IR with increased RPP ( P < 0.05 vs. HFS), ATP and PCr levels during reperfusion ( P < 0.01, P < 0.001 vs. HFS). The two approaches have distinct effects on cardiac function and energy metabolism of prediabetic female rats. Further studies are on the go to explore the mechanisms involved.

Histological Examination of Rat Heart Tissue with Chronic Diabetes

Diabetes mellitus causes structural and functional impairment of the system in the organism by affecting various organs and structures. In this study, we aimed to examine the changes in female rat heart tissue histologically by creating experimental diabetes. 16 female adult rats were used in the study. Rats were randomly divided into two groups as control and 3- month diabetes. The diabetes group was formed from subjects with blood glucose levels above 250mg/dl 72 hours after 40 mg / kg streptozotocin administration. At the end of the experiment, the heart tissues of the subjects were removed and taken into formaldehyde solution. To examine the histological structure, hematoxylin-eosin (H-E) and immunohistochemically neuronal nitric oxide syntahase (nNOS) and inducible nitric oxide syntahase (iNOS) were stained. Heart tissue sections belonging to the control group had histologically normal appearance. In the diabetes group heart tissue sections, vacuolization in some cells and eosinophilic increase in the cytoplasm of some cells were observed. The nNOS and iNOS immunreactivity was observed to be decreased in the diabetes group compared to the control group, but the decrease was not statistically significant. As a chronic disease, DM causes histological damage to the heart tissue. The resulting damage causes a decrease in nNOS and iNOS expression. It is important to maintain NOS enzyme levels in order to protect tissue from the harmful effects of diabetes and ensure normal physiological conditions.

A LOW-DOSE PROTECTIVE EFFECT OF PHYCOCYANIN ON THE TOXICITY OF DELTAMETHRIN TO VITAL ORGANS IN RATS: IN VIVO STUDY

The study highlights the histopathological alterations of the liver, kidney and heart of female rats exposed to a low dose of deltamethrin (DLM), the potential hepatoprotective, nephroprotective and cardioprotective effects of phycocyanin. Twenty-four (24) female Albino Wistar rats divided into four groups recognised as follows: Control rats received a standard diet (C). Group (PC) treated with a standard diet enriched with 3.6 ± 0.1 mg of phycocyanin per kg of granules. Group (DLM) treated with a standard diet combined with DLM in water at a concentration of 1.28 mg per kg body weight per day. The remaining group (DLM / PC) was processed by the combination of the DLM and PC scheme. The toxicity of DLM was revealed by transaminase analysis and histological observation. The association (DLM + PC) revealed a protective effect of phycocyanin as illustrated by the reduction of the concentration of serum AST and the important decrease of lesions in the tissues studied. Therefore, it shows that PC has a protective action against the toxic effects of DLM.

The role of inflammation in driving left ventricular remodeling in a pre-HFpEF model

The incidence of HFpEF continues to increase and ∼2/3 of the patient population are post-menopausal women. Unfortunately, most studies focus on the use of male animal models of remodeling. In this study, however, using female rats to set a model of pre-HFpEF, we provide insights to possible mechanisms that contribute to HFpEF development in humans that will lead us to a better understanding of the underlying pathophysiology of HFpEF.

Angiotensin-(1-7) reduces doxorubicin-induced cardiac dysfunction in male and female Sprague-Dawley rats through antioxidant mechanisms.

Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1-7) had no effect. However, adjunct Ang-(1-7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak (E) (P < 0.05) and early diastole mitral valve annulus peak velocity (e'; P < 0.001) and increased E/e' (P < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1-7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 (P < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal (P < 0.001) and malondialdehyde (P < 0.001), markers of lipid peroxidation; Ang-(1-7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1-7) increased the antioxidant enzymes SOD1 (male: P < 0.05; female: P < 0.01) and catalase (P < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1-7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity.NEW & NOTEWORTHY Ang-(1-7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.

The effect of swimming exercise on age-dependent electrophysiological changes in female rat myocardium

The effects of swimming exercise on age-associated electrical changes in female rat hearts were investigated. Four- and 24-month-old Wistar female rats were divided into three groups as follows: sedentary young, sedentary old and exercise old. Swimming exercise was performed for 8 weeks (60 min/day, 5 days/week). All recordings were taken from freshly isolated left ventricular myocytes of rat heart. Aging caused a significant increase in the size of myocytes; swimming exercise did not affect this change. The repolarization period of the action potential was prolonged in aged myocytes, but exercise training had no effect on this prolongation. Exercise suppressed the transient outward potassium currents, while the inactivation and reactivation kinetics did not change between the groups. Moreover, aging caused suppression in the inward rectifier potassium currents, and exercise increased this suppression. Consequently, changes in the action potential and potassium currents may contribute to the impaired cardiac function in the elderly female myocardium, and swimming exercise is not an effective strategy in reversing these electrical changes.

Evaluation of Glucosamine Effect Against Heart and Brain Damage Induced by Y-radiation or Aluminium Chloride in Female Rats

Abstract Glucosamine is known as anti-inflammatory, antioxidant and as neuroprotective as well as using to treat many of diseases. This work aimed to investigate the remedial effect of glucosamine (20mg/kg b.wt) against the damage induced by a single dose of γ-radiation (8Gy) or aluminium chloride (AlCl3) (100mg/kg b.wt) in the heart and brain tissues of female rats. Serum aspartate aminotransferase (AST), cholesterol, triglycerides (TGs), LDH and creatine kinase (CPK) were measured. Moreover, gene expression of amyloid protein precursor (APP) and seladin-1 were estimated in the brain tissue. Also, acetylcholinesterase activity (AChE) and p-tau protein expression were estimated in brain homogenate. Metallothioneine (MT) was estimated in the heart and brain tissues. Heart and brain histopathological examination was performed. Irradiation significantly decreased serum AST, CPK and LDH, as well as MT levels in heart and brain tissues. Also, gene expression of seladin-1 decreased. On the other hand, irradiation significantly increased serum TGs level and brain AchE activity, tau protein, and β-amyloid percursor (APP). AlCl3 administration (21 days) induced disturbance in most of the estimated parameters, especially AST, TGs, and MT. Glucosamine treatment with irradiation or AlCl3 improved most of the measured parameters. In addition, histopathological examination confirmed the biochemical results. In conclusion: Glucosamine could be used to improve the heart and brain damages induced by γ-radiation exposure or AlCl3.

Dietary n-6 and n-3 PUFA alter the free oxylipin profile differently in male and female rat hearts.

Oxylipins are bioactive lipid mediators synthesised from PUFA. The most well-known oxylipins are the eicosanoids derived from arachidonic acid (ARA), and many of them influence cardiac physiology in health and disease. Oxylipins are also formed from other n-3 and n-6 PUFA such as α-linolenic acid (ALA), EPA, DHA and linoleic acid (LA), but fundamental data on the heart oxylipin profile, and the effect of diet and sex on this profile, are lacking. Therefore, weanling female and male Sprague-Dawley rats were given American Institute of Nutrition (AIN)-93G-based diets modified in oil composition to provide higher levels of ALA, EPA, DHA, LA and LA + ALA, compared with control diets. After 6 weeks, free oxylipins in rat hearts were increased primarily by their precursor PUFA, except for EPA oxylipins, which were increased not only by dietary EPA but also by dietary ALA or DHA. Dietary DHA had a greater effect than ALA or EPA on reducing ARA oxylipins. An exception to the dietary n-3 PUFA-lowering effects on ARA oxylipins was observed for several ARA-derived PG metabolites that were higher in rats given EPA diets. Higher dietary LA increased LA oxylipins, but it had no effect on ARA oxylipins. Overall, heart oxylipins were higher in female rats, but this depended on dietary treatment: the female oxylipin:male oxylipin ratio was higher in rats provided the ALA compared with the DHA diet, with other diet groups having ratios in between. In conclusion, individual PUFA and sex have unique and interactive effects on the rat heart free oxylipin profile.

Abstract 2885: Angiotensin-(1-7) prevents doxorubicin-induced cardiotoxicity by reducing oxidative stress and fibrosis

Abstract Doxorubicin (Dox) is an effective chemotherapeutic agent for various malignancies including childhood leukemias and lymphomas. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests as cardiomyopathy with marked oxidative stress and fibrosis leading to a long-term reduction in cardiovascular function and heart failure. Adjunct therapies to mitigate Dox-induced cardiotoxicity and enhance long-term quality-of-life in cancer patients are needed, particularly for pediatric patients. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone of the renin-angiotensin system with cardioprotective properties. We investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from acute (6 week) exposure to Dox (21-24 mg/kg) in male and female juvenile rats (n = 7-10). Dox treatment reduced body/heart mass in male and female rats and co-administration of Ang-(1-7) had no effect on these morphological changes. However, co-administration of the heptapeptide hormone prevented Dox-mediated diastolic dysfunction, including decreased passive filling (E; 16%, p&amp;lt;0.05) and mitral annulus tissue movement (e'; 45% in males and 31% in females, p&amp;lt;0.001) and the subsequent increased filling pressure (E/e'; 47% in males and 43% in females, p&amp;lt;0.001). In both male and female rat hearts, Dox administration increased NADPH oxidase 4 (Nox4; 2-fold in males and females, p&amp;lt;0.05), the major Nox isozyme that generates ROS in the heart, as well as 4-hydroxynonenal (4-HNE; 7.5-fold in males and 3.5-fold in females, p&amp;lt;0.001) and malondialdehyde (MDA; 20-fold in males and 15-fold in females, p&amp;lt;0.001), markers of lipid peroxidation. Co-administration of Ang-(1-7) prevented these effects of Dox while Ang-(1-7) alone had no effect. Treatment of rats with Dox and Ang-(1-7) also increased cardiac superoxide dismutase 1 (SOD1; 4-fold in males and 5-fold in females, p&amp;lt;0.05 and p&amp;lt;0.01 respectively) and catalase (10-fold in males and 4-fold in females, p&amp;lt;0.05), further contributing to reduced oxidative stress. Oxidative stress is associated with an increase in cardiac fibrosis, a maladaptive change that exacerbates cardiac dysfunction. Treatment of male and female rats with Dox increased collagen deposition in the heart which was associated with an increase in the fibrogenic cytokine TGF-β1 and TGF-β1-activated phospho-SMAD2; co-administration of Ang-(1-7) mitigated the Dox-induced increase in fibrosis while the heptapeptide hormone alone had no effect. The anti-oxidant and anti-fibrotic effects of Ang-(1-7) may account for the improvement in diastolic function by the heptapeptide hormone, suggesting that treatment with Ang-(1-7) may serve as an effective adjuvant to improve Dox-induced cardiac dysfunction. Citation Format: Patricia E. Gallagher, Omeed Rahimi, Brian Westwood, Jay Kirby, Jasmina Varagic, Elisabeth Ann Tallant. Angiotensin-(1-7) prevents doxorubicin-induced cardiotoxicity by reducing oxidative stress and fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2885.

Influence of maternal protein malnutrition on oxidative stress and regulators of mitochondrial biogenesis in female rat hearts over succeeding generations

AimsWe sought to evaluate the effects of maternal protein restriction (LP) on oxidative balance and transcription factors for mitochondrial biogenesis in the hearts of young female rats of both the first (F1) and second (F2) generation. Main methodsWe evaluated oxidative stress biomarkers (lipid peroxidation and protein oxidation), enzymatic antioxidant defense (activity of superoxide dismutase-SOD, catalase, and glutathione-S-transferase-GST), nonenzymatic antioxidant defense (reduced glutathione-GSH and sulfhydryl groups) and gene expression of AMPK, PGC-1α and TFAM. Key findingsInterestingly, lipid peroxidation was decreased (49%, p < 0.001) in the LP-F1 group and 59% (p < 0.001) in LP-F2. In enzymatic defense, we observed increases in SOD activity in the LP-F1 group (79%, p = 0.036) and in CAT activity (approximately 40%, p = 0.041). GSH was increased in F2 in both groups (LP 546%, p < 0.0001 and in NP 491.7%, p < 0.0001). With respect to mitochondrial biogenesis gene transcription, we observed a decrease in AMPK (60%, p < 0. 0001) and an increase in PGC-1α (340%, p < 0.001) in LP compared to NP in the F1 generation. TFAM was decreased in LP-F2L compared to NP-F2L (42%, p = 0.0069) and increased in LP-F2 compared to LP-F1 (160%, p = 0.0037). SignificanceOur study contributes to knowledge of inheritance, showing that despite the potential mitochondrial ‘inheritance’ of cardiovascular damage caused by maternal malnutrition, that damage is not cross-generational and can be eliminated with proper nutrition in the F1 generation.

Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning.

We determined the impact of sex on the magnitude of cardioprotection by local and remote ischemic preconditioning (IPC and RIPC) and of ischemic/reperfused peripheral tissue mass on protection by RIPC. Hearts of female and male Lewis rats were excised, perfused with buffer, and underwent either IPC by 3 × 5/5 min global zero‐flow ischemia/reperfusion (GI/R) or time‐matched perfusion (TP) before 30/120 min GI/R. In a second approach, anesthetized female and male Lewis rats underwent RIPC, 3 × 5/5 min ischemia/reperfusion of one or both hindlimbs (1‐RIPC or 2‐RIPC), or placebo. Thirty minutes after the RIPC/placebo protocol, hearts were excised and subjected to GI/R. In female and male hearts, infarct size was less with IPC than with TP before GI/R (IPC+GI/Rfemale: 12 ± 5%; IPC+GI/Rmale: 12 ± 7% vs. TP+GI/Rfemale: 33 ± 5%; TP+GI/Rmale: 37 ± 7%, P < 0.001). With 2‐RIPC, infarct size was less than with 1‐RIPC in female and male rat hearts, respectively (2‐RIPC+GI/Rfemale: 15 ± 5% vs. 1‐RIPC+GI/Rfemale: 22 ± 7%, P = 0.026 and 2‐RIPC+GI/Rmale: 16 ± 5% vs. 1‐RIPC+GI/Rmale: 22 ± 8%, P = 0.016). Infarct size after the placebo protocol and GI/R was not different between female and male hearts (36 ± 8% vs. 34 ± 5%). Sex is no determinant of IPC‐ and RIPC‐induced cardioprotection in isolated Lewis rat hearts. RIPC‐induced cardioprotection is greater with greater mass of ischemic/reperfused peripheral tissue.

In-situ optical assessment of rat epicardial kinematic parameters reveals frequency-dependent mechanic heterogeneity related to gender

BackgroundGender-related cardiac mechanics following the electrical activity has been investigated from basic to clinical research, but results are still controversial. The aim of this work is to study the gender related cardiac mechanics and to focus on its heart rate dependency. MethodsWe employed 12 Sprague Dawley rats (5 males and 7 females) of the same age and, through a novel high resolution artificial vision contactless approach, we evaluated in-situ cardiac kinematic. The hearts were paced on the right atria appendage via cathodal stimuli at rising frequency. ResultsKinematic data obtained at rising pacing rates are different between male and female rat hearts: male tended to maintain the same level of cardiac force, energy and contractility, while female responded with an increment of such parameters at increasing heart rate. Female hearts preserved their pattern of contraction and epicardial torsion (vorticity) at rising pacing rates compared to male. Furthermore, we observed a difference in the mechanical restitution: systolic time vs. diastolic time, as an index of cardiac performance, reached higher value in male compared to female hearts. ConclusionOur innovative technology was capable to evaluate in-situ rat epicardial kinematic at high stimulation frequency, revealing that male preserved kinematic parameters but varying the pattern of contraction/relaxation. On the contrary, female preserved the pattern of contraction/relaxation increasing kinematic parameters.

Long‐term consequences of severe food restriction on the heart of female Fischer rats

IntroductionIndividuals under voluntary (e.g., anorexia, crash diets) or involuntary (e.g., very low food security) severe food restriction (sFR) are at increased risk for developing cardiovascular disease during the sFR period and also long term well after the sFR period has ended. During the sFR period patients present long QT interval, arrhythmia, hypotension and bradycardia and sometimes death, which is primarily due to heart failure. Unfortunately, Little is known, however, almost nothing is known about the heart function when these individuals recoveries the body weight. Cardiovascular disease due to earlier exposure to sFR is an underappreciated and understudied problem and there are no Aim: ‐consequencesof sFR on heart structure and function known therapeutic strategies designed to prevent or reverse the increased risk after recovery from the sFR period(s).MethodsFemale Fischer rats with 3‐month‐old were divided in a control (CT) (ad libitum regular chow; n=18) and sFR (60% reduction of daily food intake, n=18) group. After 2 weeks all rats received regular chow ad libitum for 3 months. The control and sFR rats were then divided into three groups each and infused with vehicle (n=8), in a bolus infusion of angiotensin II (400ng/Kg – 0.2mL; n=6), or subjected to ischemia‐reperfusion using a Langendorff preparation (n=4). At the end of the experiment, the rats were sacrificed and the hearts were removed for histology.ResultsAfter 14 of sFR body weight was reduced by 18%, Mean arterial pressure (p=0.03), heart rate (p=0.03) and wet heart weight (p=0.009) were reduced. After 3 mo of refeeding, body weight, MAP, HR, and wet heart weight were indistinguishable from the control animals. Despite normalization of some parameters,, 3 months of refeeding, analysis of H&amp;E stained myocardium tissue in vehicle‐treated rats revealed that parallel orientation of myofiber and clear striations present in normal cardiomyocytes were lost in sFR‐refed animals indicating severe cardiac damage. Uneven blood‐filling of the vessels of the microcirculatory and prominent interstitial edema of the myocardium was observed. The cardiomyocytes were polymorphic and single cardiomyocytes also found to be atrophied. Infusion of angiotensin II to sFR‐refed animals, but not to control animals, resulted in the occurrence of focal necrotic lesions causing by multiple contractures of cardiomyocytes, indicating cardiomyocytes had disrupted of calcium homeostasis and increased calcium sensitivityof sFR‐refed animals. The magnitude of ischemia/reperfusion‐induced damage was also greater in sFR‐refed animals compared to control animals in Langendorff preparations. After ischemia/reperfusion injury, along with deeply eosinophilic myofibers, large amounts of necrotic cardiomyocytes were found in sFR‐refed rats, but not in control.ConclusionDespite normalization of body weight, blood pressure, heart rate and wet heart weight after 3 months of refeeding, the hearts from animals subjected to severe food restriction are severely damaged. These findings suggest individuals who have recovered from prior exposure to a period of sFR are at increased risk of developing cardiovascular disease.Support or Funding InformationNIH 1R01HL119380 (KS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.