Quantification correction for free-breathing myocardial T mapping in mice using a recursively derived description of a T* relaxation pathway.

Background: Fast and accurate T mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T relaxation pathway. In this study, we present an improved quantification method for T using a newly derived formalism of a T* relaxation pathway.

Fast myocardial T mapping in mice using k-space weighted image contrast and a Bloch simulation-optimized radial sampling pattern.

Purpose: T dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T mapping sequence, which paves the way to cardiac T dispersion quantification within the limited measurement time of an in vivo study in small animals.

Mitofusin 2 Is Essential for IP-Mediated SR/Mitochondria Metabolic Feedback in Ventricular Myocytes.

Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP) by activating their membrane-bound receptors. We have previously demonstrated that IP-mediated sarcoplasmic reticulum (SR) Ca release results in mitochondrial Ca uptake and activation of ATP production.

Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca2+ uptake through the mitochondrial ryanodine receptor in cardiac myocytes.

Aims: Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms.

Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is an entity of PH that not only limits patients quality of life but also causes significant morbidity and mortality. The treatment of choice is pulmonary endarterectomy. However numerous patients do not qualify for pulmonary endarterectomy or present with residual vasculopathy post pulmonary endarterectomy and require specific vasodilator treatment.

Metformin Protects Kidney Cells From Insulin-Mediated Genotoxicity In Vitro and in Male Zucker Diabetic Fatty Rats.

Hyperinsulinemia is thought to enhance cancer risk. A possible mechanism is induction of oxidative stress and DNA damage by insulin, Here, the effect of a combination of metformin with insulin was investigated in vitro and in vivo. The rationales for this were the reported antioxidative properties of metformin and the aim to gain further insights into the mechanisms responsible for protecting the genome from insulin-mediated oxidative stress and damage.

Eya4 Induces Hypertrophy via Regulation of p27kip1.

Background: E193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy.

Methods And Results: In this study, we first show Eya4 and E193 alter the expression of p27(kip1) in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193.

Monitoring of monocyte recruitment in reperfused myocardial infarction with intramyocardial hemorrhage and microvascular obstruction by combined fluorine 19 and proton cardiac magnetic resonance imaging.

Background: Monocytes and macrophages are indispensable in the healing process after myocardial infarction (MI); however, the spatiotemporal distribution of monocyte infiltration and its correlation to prognostic indicators of reperfused MI have not been well described.

Methods And Results: With combined fluorine 19/proton ((1)H) magnetic resonance imaging, we noninvasively visualized the spatiotemporal recruitment of monocytes in vivo in a rat model of reperfused MI. Blood monocytes were labeled by intravenous injection of (19)F-perfluorocarbon emulsion 1 day after MI.

Insulin-mediated oxidative stress and DNA damage in LLC-PK1 pig kidney cell line, female rat primary kidney cells, and male ZDF rat kidneys in vivo.

Hyperinsulinemia, a condition with excessively high insulin blood levels, is related to an increased cancer incidence. Diabetes mellitus is the most common of several diseases accompanied by hyperinsulinemia. Because an elevated kidney cancer risk was reported for diabetic patients, we investigated the induction of genomic damage by insulin in LLC-PK1 pig kidney cells, rat primary kidney cells, and ZDF rat kidneys.

Estrogen and estrogen receptors in cardiovascular oxidative stress.

The cardiovascular system of a premenopausal woman is prepared to adapt to the challenges of increased cardiac output and work load that accompany pregnancy. Thus, it is tempting to speculate whether enhanced adaptability of the female cardiovascular system might be advantageous under conditions that promote cardiovascular disease. In support of this concept, 17β-estradiol as the major female sex hormone has been shown to confer protective cardiovascular effects in experimental studies.

The estrogen receptor-α is required and sufficient to maintain physiological glucose uptake in the mouse heart.

Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate estrogen receptors (ERs) ERα and ERβ. Because female sex hormones enhance global glucose use and because myocardial function and mass are tightly linked to cardiac glucose metabolism, we tested the hypothesis that expression and activation of the ERα might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography was strongly impaired in ovariectomized compared with gonadal intact female C57BL/6JO mice.

Both estrogen receptor subtypes, ERα and ERβ, prevent aldosterone-induced oxidative stress in VSMC via increased NADPH bioavailability.

Activation of vascular mineralocorticoid (MR) or estrogen receptors (ER) exerts opposing effects on vascular remodeling. As we have previously shown, activation of either estrogen receptor subtype, ERα or ERβ, is fully sufficient to attenuate vascular remodeling in aldosterone salt-treated rats. To further elucidate the underlying mechanism(s) we tested the hypothesis that ER and MR activation might differentially modulate vascular reactive oxygen species (ROS) generation.

Medroxyprogesterone acetate aggravates oxidative stress and left ventricular dysfunction in rats with chronic myocardial infarction.

The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17β-estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI).

Differential effects of 17beta-estradiol and of synthetic progestins on aldosterone-salt-induced kidney disease.

Unlabelled: Elevated mineralocorticoid levels and female sex hormones have been shown to confer opposing effects on renal injury, but their combined effects are still unknown.

Objective: Identify the function of estrogens and of different synthetic progestins on aldosterone salt-mediated renal disease.

Methods: The role of 17beta-estradiol, medroxyprogesterone acetate (MPA), and drospirenone during renal injury was studied in Wistar rats subjected to uni-nephrectomy plus aldosterone salt treatment.

Genetic and pharmacologic strategies to determine the function of estrogen receptor alpha and estrogen receptor beta in cardiovascular system.

Background: The biological functions of estrogens extend beyond the female and male reproductive tract, affecting the cardiovascular and renal systems. Traditional views on the role of postmenopausal hormone therapy (HT) in protecting against heart disease, which were challenged by clinical end point studies that found adverse effects of combined HT, are now being replaced by more differentiated concepts suggesting a beneficial role of early and unopposed HT that does not include a progestin.

Objective: We reviewed recent insights, concepts, and research results on the biology of both estrogen receptor (ER) subtypes, ERalpha and ERbeta, in cardiac and vascular tissues.

Ligand-dependent activation of ER{beta} lowers blood pressure and attenuates cardiac hypertrophy in ovariectomized spontaneously hypertensive rats.

Aims: The biological effects of oestrogens are mediated by two different oestrogen receptor (ER) subtypes, ERalpha and ERbeta, which might play different, redundant, or opposing roles in cardiovascular disease. Previously, we have shown that the selective ERalpha agonist 16alpha-LE2 improves vascular relaxation, attenuates cardiac hypertrophy, and increases cardiac output without lowering elevated blood pressure in spontaneously hypertensive rats (SHR). Because ERbeta-deficient mice exhibit elevated blood pressure and since the ERbeta agonist 8beta-VE2 attenuated hypertension in aldosterone-salt-treated rats, we have now tested the hypothesis that the isotype-selective ERbeta agonist 8beta-VE2 might be capable of lowering elevated blood pressure in ovariectomized SHR.

Both estrogen receptor subtypes, alpha and beta, attenuate cardiovascular remodeling in aldosterone salt-treated rats.

Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart disease requires more precise information on the role of both estrogen receptor (ER) subtypes, ERalpha and ERbeta. Therefore, we determined whether selective activation of ERalpha or of ERbeta would confer redundant, specific, or opposing effects on cardiovascular remodeling in aldosterone salt-treated rats.

Medroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats.

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment.

Increased mortality and aggravation of heart failure in estrogen receptor-beta knockout mice after myocardial infarction.

Background: Lower mortality rates among women with chronic heart failure than among men may depend in part on the action of female sex hormones, especially estrogens. The biological effects of estrogens are mediated by 2 distinct estrogen receptor (ER) subtypes (ERalpha and ERbeta). The present study was undertaken to determine the role of ERbeta in the development of chronic heart failure after experimental myocardial infarction (MI).

Pioglitazone reverses down-regulation of cardiac PPARgamma expression in Zucker diabetic fatty rats.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPARgamma in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPARgamma agonist pioglitazone or placebo from 12 to 24 weeks of age.