Beneficial impact of cardiac heavy metal scavenger metallothionein in sepsis-provoked cardiac anomalies dependent upon regulation of endoplasmic reticulum stress and ferroptosis but not autophagy.

Aims: Sepsis represents a profound proinflammatory response with a major contribution from oxidative injury. Here we evaluated possible impact of heavy metal scavenger metallothionein (MT) on endotoxin lipopolysaccharide (LPS)-induced oxidative stress, endoplasmic reticulum (ER) stress, autophagy, and ferroptosis enroute to myocardial injury along with interplay among these stress domains.

Materials And Methods: Echocardiographic, cardiomyocyte mechanical and intracellular Ca responses were monitored in myocardia from WT and transgenic mice with cardiac-selective MT overexpression challenged with LPS.

Ablation of Akt2 protects against lipopolysaccharide-induced cardiac dysfunction: role of Akt ubiquitination E3 ligase TRAF6.

Lipopolysaccharide (LPS), an essential component of the outer membrane of Gram-negative bacteria, plays a pivotal role in myocardial anomalies in sepsis. Recent evidence has depicted a role of Akt in LPS-induced cardiac sequelae although little information is available with regard to the contribution of Akt isoforms in the endotoxin-induced cardiac dysfunction. This study examined the effect of Akt2 knockout on LPS-induced myocardial contractile dysfunction and the underlying mechanism(s) with a focus on TNF receptor-associated factor 6 (TRAF6).

Apelin administration ameliorates high fat diet-induced cardiac hypertrophy and contractile dysfunction.

Apelin has been recognized as an adipokine that plays an important role in regulating energy metabolism and is credited with antiobesity and antidiabetic properties. This study was designed to examine the effect of exogenous apelin on obesity-associated cardiac dysfunction. Oral glucose tolerance test, echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were assessed in adult C57BL/6J mice fed - low or a - high-fat diet for 24weeks followed by apelin treatment (100nmol/kg, i.

Cardiomyocyte-specific deletion of endothelin receptor A rescues aging-associated cardiac hypertrophy and contractile dysfunction: role of autophagy.

Cardiac aging is manifested as cardiac remodeling and contractile dysfunction although precise mechanisms remain elusive. This study was designed to examine the role of endothelin-1 (ET-1) in aging-associated myocardial morphological and contractile defects. Echocardiographic and cardiomyocyte contractile properties were evaluated in young (5-6 months) and old (26-28 months) C57BL/6 wild-type and cardiomyocyte-specific ET(A) receptor knockout (ETAKO) mice.

Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy.

Aging is often accompanied with geometric and functional changes in the heart, although the underlying mechanisms remain unclear. Recent evidence has described a potential role of Akt and autophagy in aging-associated organ deterioration. This study was to examine the impact of cardiac-specific Akt activation on aging-induced cardiac geometric and functional changes and underlying mechanisms involved.

Insulin-like growth factor I (IGF-1) deficiency ameliorates sex difference in cardiac contractile function and intracellular Ca(2+) homeostasis.

Sex difference in cardiac contractile function exists which may contribute to the different prevalence in cardiovascular diseases between genders. However, the precise mechanisms of action behind sex difference in cardiac function are still elusive. Given that sex difference exists in insulin-like growth factor I (IGF-1) cascade, this study is designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on sex difference in cardiac function.

Effects of a long-term treatment with an antioxidant pyridoindole on vascular responsiveness in diabetes-induced aging rats.

Impaired vascular reactivity is a hallmark of cardiovascular diseases induced by diabetes, which is also an accelerated aging model. This study was designed to investigate the effect of chronic treatment of stobadine, a pyridoindole antioxidant, on vascular responsiveness in diabetic animals. Age- (13-week old) and gender-matched Wistar rats were randomly divided into control and diabetic groups.

Endoplasmic reticulum chaperon tauroursodeoxycholic acid alleviates obesity-induced myocardial contractile dysfunction.

ER stress is involved in the pathophysiology of obesity although little is known about the role of ER stress on obesity-associated cardiac dysfunction. This study was designed to examine the effect of ER chaperone tauroursodeoxycholic acid (TUDCA) on obesity-induced myocardial dysfunction. Adult lean and ob/ob obese mice were treated with TUDCA (50mg/kg/day, p.

Sex difference in alcoholism: who is at a greater risk for development of alcoholic complication?

Aims: Alcohol abuse and alcoholism are among the major medical problems afflicting both men and women. While men display a higher prevalence for alcoholism, it is women who suffer a much greater risk for alcoholism-associated bodily damage. Although women generally consume less alcohol compared to men, females usually suffer more severe brain and other organ damage following binge or chronic alcohol abuse.

Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis.

Sepsis is characterized by systematic inflammation where oxidative damage plays a key role in organ failure. This study was designed to examine the impact of the antioxidant metallothionein (MT) on lipopolysaccharide (LPS)-induced cardiac contractile and intracellular Ca(2+) dysfunction, oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Mechanical and intracellular Ca(2+) properties were examined in hearts from FVB and cardiac-specific MT overexpression mice treated with LPS.

Effect of 17beta-oestradiol replacement on vascular responsiveness in ovariectomized diabetic rats.

1. Women with functional ovaries exhibit a gender advantage in terms of the prevalence of cardiovascular diseases. However, whether this gender bias pertains in diabetes is unknown.

Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis.

One key mechanism for endothelial dysfunction is endothelial NO synthase (eNOS) uncoupling, whereby eNOS generates O(2)(*-) rather than NO because of deficient eNOS cofactor tetrahydrobiopterin (BH4). This study was designed to examine the effect of BH4 deficiency on cardiac morphology and function, as well as the impact of metallothionein (MT) on BH4 deficiency-induced abnormalities, if any. Friend virus B (FVB) and cardiac-specific MT transgenic mice were exposed to 2,4-diamino-6-hydroxy-pyrimidine (DAHP; 10 mmol/L, 3 weeks), an inhibitor of the BH4 synthetic enzyme GTP cyclohydrolase I.

Herbal and traditional Chinese medicine for the treatment of cardiovascular complications in diabetes mellitus.

Cardiovascular diseases, the number one causes of death worldwide, are responsible for the majority of the increased morbidity and mortality seen in patients with diabetes mellitus. Useful therapies for diabetes include lifestyle modification and drugs to lower conventional cardiovascular risk factors, such as metformin, thiazolindinedione, sulfonylureas and evidence-based drugs. These hypoglycemic or antihyperglycemic agents are widely used either for monotherapy or in combination to improve glycemic control and to slow disease progression associated with a decline in pancreatic function in diabetic patients.

Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction.

Circulating insulin-like growth factor-1 (IGF-1) levels are linked to cardiac performance and lifespan. However, the role of IGF-1 levels in aging-associated cardiac dysfunction has not been defined. This study was designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on aging-induced cardiomyocyte contractile and intracellular Ca(++) dysfunction.

High-fat diet-induced obesity leads to resistance to leptin-induced cardiomyocyte contractile response.

Levels of the obese gene product leptin are often elevated in obesity and may contribute to obesity-induced cardiovascular complications. However, the role of leptin in obesity-associated cardiac abnormalities has not been clearly defined. This study was designed to determine the influence of high-fat diet-induced obesity on cardiac contractile response of leptin.

Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme.

Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca(2+) cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes.

Gender disparity of streptozotocin-induced intrinsic contractile dysfunction in murine ventricular myocytes: role of chronic activation of Akt.

1. Clinical, epidemiological and experimental evidence suggests a 'female advantage' in the progression of cardiovascular diseases, including diabetic cardiomyopathy. It is speculated that this 'gender bias' may be due to gender-related differences in sex hormones and intrinsic myocardial contractile properties.

Sex difference in cardiomyocyte function in normal and metallothionein transgenic mice: the effect of diabetes mellitus.

Evidence suggests a sex difference in intrinsic physiological and diabetic myocardial contractile function related to antioxidant properties of female ovarian hormones. This study was designed to examine the effect of cardiac overexpression of antioxidant metallothionein on intrinsic and diabetic cardiomyocyte function. Weight-matched wild-type (FVB) and metallothionein transgenic mice of both sexes were made diabetic with streptozotocin (220 mg/kg).

High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus.

Diabetic cardiomyopathy is characterized by cardiac dysfunction. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse cardiomyocytes. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg ip).

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function.

Insulin-like growth factor-I (IGF-1) ameliorates cardiac dysfunction in diabetes although the mechanism of action remains poorly understood. This study examined the role of PI-3 kinase/Akt/mammalian target of rapamycin (mTOR) and calcineurin pathways in cardiac effects of IGF-1 against glucose toxicity. Adult rat ventricular myocytes were cultured for 8 h with either normal (NG, 5.

Oxidative stress and stress signaling: menace of diabetic cardiomyopathy.

Cardiovascular disease is the most common cause of death in the diabetic population and is currently one of the leading causes of death in the United States and other industrialized countries. The health care expenses associated with cardiovascular disease are staggering, reaching more than 350 billion dollars in 2003. The risk factors for cardiovascular disease include high fat/cholesterol levels, alcoholism, smoking, genetics, environmental factors and hypertension, which are commonly used to gauge an individual's risk of cardiovascular disease and to track their progress during therapy.

Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification.

Evidence suggests that aging, per se, is a major risk factor for cardiac dysfunction. Oxidative modification of cardiac proteins by non-enzymatic glycation, i.e.