Influence of age and sex on physical, cardiac electrical and functional alterations in progressive hyperoxia treatment: A time course study in a murine model.

Oxygen supplementation is a widely used treatment for ICU patients. However, it can lead to hyperoxia, which in turn can result in oxidative stress, cardiac remodeling, and even mortality. This paper expands upon previous research conducted by our lab to establish time-dependent cardiac changes under hyperoxia. In this study, both young and aged mice (male and female) underwent 72 h of hyperoxia exposure and were monitored at 24-hour intervals for cardiac electrophysiological and functional parameters using ECG and electrocardiogram data. Our analysis showed that young male mice experienced significant weight loss as well as significant lung edema by 48 h. Although young male mice were highly susceptible to physical changes, they were resistant to early cardiac functional and electrophysiological changes compared to the other groups. Both young and aged female and aged males developed functional impairments by 24 h of hyperoxia exposure. Furthermore, sex and age differences were noted in the onset of electrophysiological changes. While some groups could resist early cardiac remodeling, our data suggests that 72 h of hyperoxia exposure is sufficient to induce significant cardiac remodeling across all age and sex groups. Our data establishes that time-dependent cardiac changes due to oxygen supplementation can have devastating consequences even with short exposure periods. These findings can aid in developing clinical practices for individuals admitted to the ICU by elucidating the impact of aging, sex, and length of stay under mechanical ventilation to limit hyperoxia-induced cardiac remodeling.

Influence of Age on Hyperoxia-Induced Cardiac Pathophysiology in Type 1 Diabetes Mellitus (T1DM) Mouse Model.

Mechanical ventilation often results in hyperoxia, a condition characterized by excess SpO2 levels (>96%). Hyperoxia results in changes in the physiological parameters, severe cardiac remodeling, arrhythmia development, and alteration of cardiac ion channels, all of which can point toward a gradual increase in the risk of developing cardiovascular disease (CVD). This study extends the analysis of our prior work in young Akita mice, which demonstrated that exposure to hyperoxia worsens cardiac outcomes in a type 1 diabetic murine model as compared to wild-type (WT) mice. Age is an independent risk factor, and when present with a major comorbidity, such as type 1 diabetes (T1D), it can further exacerbate cardiac outcomes. Thus, this research subjected aged T1D Akita mice to clinical hyperoxia and analyzed the cardiac outcomes. Overall, aged Akita mice (60 to 68 weeks) had preexisting cardiac challenges compared to young Akita mice. Aged mice were overweight, had an increased cardiac cross-sectional area, and showed prolonged QTc and JT intervals, which are proposed as major risk factors for CVD like intraventricular arrhythmias. Additionally, exposure to hyperoxia resulted in severe cardiac remodeling and a decrease in Kv 4.2 and KChIP2 cardiac potassium channels in these rodents. Based on sex-specific differences, aged male Akita mice had a higher risk of poor cardiac outcomes than aged females. Aged male Akita mice had prolonged RR, QTc, and JT intervals even at baseline normoxic exposure. Moreover, they were not protected against hyperoxic stress through adaptive cardiac hypertrophy, which, at least to some extent, is due to reduced cardiac androgen receptors. This study in aged Akita mice aims to draw attention to the clinically important yet understudied subject of the effect of hyperoxia on cardiac parameters in the presence of preexisting comorbidities. The findings would help revise the provision of care for older T1D patients admitted to ICUs.

Impact of age and sex on hyperoxia-induced cardiovascular pathophysiology.

Hyperoxia is characterized by pronounced inflammatory responses, pulmonary cell apoptosis, and adverse cardiac remodeling due to an excess supply of oxygen. Hyperoxic episodes are frequent in mechanically ventilated patients and are associated with in-hospital mortality. This study extends the analysis of prior published research by our group as it investigates the influence of age in male and female rodents exposed to hyperoxic conditions. Age is an independent cardiovascular risk factor, often compounded by variables like obesity, diabetes, and a decline in sex hormones and their receptors. This study simulates clinical hyperoxia by subjecting rodents to > 90 % of oxygen for 72 h and compares the changes in cardiac structural and functional parameters with those exposed to normal air. While in both sexes conduction abnormalities with ageing were discernible, aged females owing to their inherent higher baseline QTc, were at a higher risk of developing arrhythmias as compared to age-matched males. Quantitative real-time RT-PCR and western blot analysis reflected altered expression of cardiac potassium channels, resulting in conduction abnormalities in aged female rodents. Unaffected by age and sex, hyperoxia-treated mice had altered body composition, as evidenced by a considerable reduction in body weight. Interestingly, compensatory hypertrophy observed as a protective mechanism in young males was absent in aged males, whereas protection of hearts from hyperoxia-induced cardiac hypertrophy was absent in aged female mice, both of which may be at least in part due to a reduction in sex steroid receptors and the systemic steroid levels. Finally, statistical analysis revealed that hyperoxia had the greatest impact on most of the cardiac parameters, followed by age and then sex. This data established an imperative finding that can change the provision of care for aged individuals admitted to ICU by elucidating the impact of intrinsic aging on hyperoxia-induced cardiac remodeling.

The implications of hyperoxia, type 1 diabetes and sex on cardiovascular physiology in mice.

Oxygen supplementation, although a cornerstone of emergency and cardiovascular medicine, often results in hyperoxia, a condition characterized by excessive tissue oxygen which results in adverse cardiac remodeling and subsequent injurious effects to physiological function. Cardiac remodeling is further influenced by various risk factors, including pre-existing conditions and sex. Thus, the purpose of this experiment was to investigate cardiac remodeling in Type I Diabetic (Akita) mice subjected to hyperoxic treatment. Overall, we demonstrated that Akita mice experience distinct challenges from wild type (WT) mice. Specifically, Akita males at both normoxia and hyperoxia showed significant decreases in body and heart weights, prolonged PR, QRS, and QTc intervals, and reduced %EF and %FS at normoxia compared to WT controls. Moreover, Akita males largely resemble female mice (both WT and Akita) with regards to the parameters studied. Finally, statistical analysis revealed hyperoxia to have the greatest influence on cardiac pathophysiology, followed by sex, and finally genotype. Taken together, our data suggest that Type I diabetic patients may have distinct cardiac pathophysiology under hyperoxia compared to uncomplicated patients, with males being at high risk. These findings can be used to enhance provision of care in ICU patients with Type I diabetes as a comorbid condition.

Hyperoxia-induced cardiotoxicity and ventricular remodeling in type-II diabetes mice.

Hyperoxia, or supplemental oxygen, is regularly used in the clinical setting for critically ill patients in ICU. However, several recent studies have demonstrated the negative impact of this treatment in patients in critical care, including increased rates of lung and cardiac injury, as well as increased mortality. The purpose of this study was to determine the predisposition for arrhythmias and electrical remodeling in a type 2 diabetic mouse model (db/db), as a result of hyperoxia treatment. For this, db/db and their heterozygous controls were treated with hyperoxia (> 90% oxygen) or normoxia (normal air) for 72-h. Immediately following hyperoxia or normoxia treatments, mice underwent surface ECG. Excised left ventricles were used to assess ion channel expression, including for Kv1.4, Kv1.5, Kv4.2, and KChIP2. Serum cardiac markers were also measured, including cardiac troponin I and lactate dehydrogenase. Our results showed that db/db mice have increased sensitivity to arrhythmia. Normoxia-treated db/db mice displayed features of arrhythmia, including QTc and JT prolongation, as well as QRS prolongation. A significant increase in QRS prolongation was also observed in hyperoxia-treated db/db mice, when compared to hyperoxia-treated heterozygous control mice. Db/db mice were also shown to exhibit ion channel dysregulation, as demonstrated by down-regulation in Kv1.5, Kv4.2, and KChIP2 under hyperoxia conditions. From these results, we conclude that: (1) diabetic mice showed distinct pathophysiology, when compared to heterozygous controls, both in normoxia and hyperoxia conditions. (2) Diabetic mice were more susceptible to arrhythmia at normal air conditions; this effect was exacerbated at hyperoxia conditions. (3) Unlike in heterozygous controls, diabetic mice did not demonstrate cardiac hypertrophy as a result of hyperoxia. (4) Ion channel remodeling was also observed in db/db mice under hyperoxia condition similar to its heterozygous controls.

Resveratrol and Omega-3 Fatty Acid: Its Implications in Cardiovascular Diseases.

The present review aims at summarizing the major therapeutic roles of resveratrol and omega-3 fatty acids (O3FAs) along with their related pathways. This article reviews some of the key studies involving the health benefits of resveratrol and O3FAs. Oxidative stress has been considered as one of the most important pathophysiological factors associated with various cardiovascular disease conditions. Resveratrol, with the potent antioxidant and free radical scavenging properties, has been proven to be a significantly protective compound in restoring the normal cardiac health. A plethora of research also demonstrated the reduction of the risk of coronary heart disease, hypertension, and stroke, and their complications by O3FAs derived from fish and fish oils. This review describes the potential cardioprotective role of resveratrol and O3FAs in ameliorating the endoplasmic reticulum stress.

Using quantitative real-time reverse transcriptase polymerase chain reaction to validate gene regulation by PTTG.

Pituitary tumor transforming gene is an important gene which is involved in many cellular functions including cell division, DNA repair, organ development, expression, and secretion of various angiogenic and metastatic factors. Overexpression of this gene has also been reported in many cancers. Understanding the molecular pathways induced by this oncogene is therefore important not only to understand the development of the disease but also for proper diagnosis and treatment. Gene profiling is an excellent tool to identify the genetic mechanisms, networks, and pathways associated with a particular disease. Oligo-nucleotide microarrays can be everybody's choice as a first step to identify the global expression of genes involved in the study of interest. Each technique has its own limitation. Therefore, further confirmation of the results with a different technique is always necessary. Quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) is one of the widely used and best described techniques to confirm the microarray data. Here, we describe the qRT-PCR techniques for gene profiling studies and the methods used for the analysis of the output data for further studies.

PTTG: an important target gene for ovarian cancer therapy.

Pituitary tumor transforming gene (PTTG), also known as securin is an important gene involved in many biological functions including inhibition of sister chromatid separation, DNA repair, organ development, and expression and secretion of angiogenic and metastatic factors. Proliferating cancer cells and most tumors express high levels of PTTG. Overexpression of PTTG in vitro induces cellular transformation and development of tumors in nude mice. The PTTG expression levels have been correlated with tumor progression, invasion, and metastasis. Recent studies show that down regulation of PTTG in tumor cell lines and tumors in vivo results in suppression of tumor growth, suggesting its important role in tumorigenesis. In this review, we focus on PTTG structure, sub-cellular distribution, cellular functions, and role in tumor progression with suggestions on possible exploration of this gene for cancer therapy.