Browsing by Subject "Cardiovascular Diseases"
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Item Mitophagy in Heart Failure-A Selective Autophagic Degradation of Mitochondria(2009-06-05) Yang, Kai-Chun (Daniel); Hill, Joseph A.INTRODUCTION: Cardiovascular disease is associated with declines in mitochondrial function. Autophagy is a lysosomal-dependent process through which cytoplasmic proteins and organelles can be degraded and has recently been shown to participate in remodeling of the myocardium in a variety of cardiac pathologies. Autophagy can be either non-selective or selective for damaged protein aggregates or organelles. Reactive oxygen species (ROS) generated in mitochondria causes mitochondrial permeability transition (MPT) and induces selective degradation of mitochondria (mitophagy). We hypothesized that mitophagy contributes to remodeling of the heart under severe oxidative stress. METHODS: Mice were subjected to hemodynamic overload by severe thoracic aortic constriction (sTAC). qPCR was used to measure the abundance of mtDNA relative to nuclear DNA. Changes in proteins and cardiac function were also assessed. RESULTS: Decreases in mtDNA abundance were time dependent after sTAC (-47%at day 2, p<0.1; -73%at day 4, p<0.05) (n=2 each) and correlated with increased mortality (37% at day 2; 75% at day 4). The decline in mtDNA was greater in the basal septum (-88%p<0.01) than in the left ventricular free wall (- 42% p<0.15) (n=4) day 8 post-sTAC. The basal septum is where we have observed the largest increases in autophagic activity and protein carbonylation, a ROS-mediated protein modification. Daily injections with cyclosporine (CsA), an inhibitor of both MPT and calcineurin, blunted load-induced mtDNA loss (-28%ith CsA vs -83%with vehicle treatment, p<0.01) (n=3) at 4 days post-sTAC. Furthermore, CsA improved survival at 4 days-post sTAC (40% mortality with CsA vs 75% with vehicle) (n=5-8). Mice with increased ROS generation due to a disruption of the cardiac isoform of the cytochrome-c oxidase subunit COXVIaH were more sensitive to pressure overload-induced loss of mtDNA and mitochondrial proteins. CONCLUSION: MtDNA abundance declines in this model of load-induced heart failure and is associated with increased autophagic activity and ROS generation. Short-term application of CsA can blunt mtDNA loss and improve survival.Item The Relationship of Inflammatory Markers to Cognitive Function in a Population-Based Sample(2010-11-02T18:10:17Z) Bernardo, Keith Alan; Lacritz, Laura Ph.D., ABPPC-reactive protein (CRP), Interleukin-18 (IL-18), Monocyte chemoattractant protein (MCP-1), and Lipoprotein-associated phospholipase (Lp-PLA2) are pro-inflammatory blood markers that appear to play critical roles in atherosclerosis and vascular disease, and have been linked to Alzheimer’s Disease, vascular dementia, and subclinical levels of cognitive decline. The present study investigated the relationship of these four inflammatory markers to cognitive function prospectively, and examined the potential impact of vascular risk factors (i.e., hypertension, hyperlipidemia, smoking status, alchol intake, diabetes mellitus, waist circumference, Cystatin C) and APOE 4 as mediators of cognitive function. METHOD AND RESULTS: Participants include 1904 individuals with CRP, IL-18, MCP-1, and Lp-PLA2, vascular risk factor and APOE 4 data collected as part of the Dallas Heart Study I initiated in 1999, who returned to the Dallas Heart Study II (8 years later) who completed the Montreal Cognitive Assessment (MoCA) as part of a larger clinical research protocol. A significant yet weak correlation was found for Lp-PLA2 (r=.09, p<.01) and MoCA scores, with significant correlations only for men (r=.24, p<.01). None of the other inflammatory markers were associated with MoCA scores. An increased number of vascular risk factors was not related to lower MoCA total scores [F(5,1621)=1.56, p=.168)]. The presence of the APOE 4 allele did not impact the relationship between concentrations of blood markers and cognitive function as hypothesized. In logistic regression analysis, only the demographic variables of Caucasian race and education were significant, and decreased the odds of membership into lowest MoCA tertile group. CONCLUSIONS: Results did not support a relationship between mid-life inflammation and vascular risk factors and later cognitive function in this healthy, middle-aged sample. Demographic factors were the only consistent variables associated with cognitive performance. The minimum level of significant inflammation in this sample may have attenuated the results. Follow-up studies to examine progression of inflammation and vascular risk in relation to cognitive function will help to further examine these relationships.Item Subclinical Atherosclerosis and Cognitive Functioning in a Population-Based Sample(2010-11-02T18:18:59Z) Rossetti, Heidi Christine; Lacritz, LauraClinical risk factors for and signs of atherosclerosis have been linked to Alzheimer disease and milder forms of cognitive impairment. This study examines the relationship between subclinical atherosclerosis and cognition in a sample from the Dallas Heart Study (DHS), a population-based study of cardiovascular disease, who were followed 8 years later (DHS-II); N = 1904, mean age = 42.9, SD = 10.5, range 8-65. Weanalyzed atherosclerosis data from DHS-I participants who had completed the Montreal Cognitive Assessment (MoCA) in DHS-II. The relationship between MoCA scores, coronary artery calcium (CAC), abdominal aortic plaque, and abdominal aortic wall thickness (AWT) was examined in the group as a whole, and in relation to age and ApoE4 allele status. Indirect measures of atherosclerosis (diabetes, hypertension, hypercholesterolemia, abdominal obesity) were also examined. Logistic regression was used to examine the association between direct and indirect measures of subclinical atherosclerosis and cognitive function, adjusting for other correlates of cognition. CAC (N = 1414, rho = -.06), abdominal AWT (N = 1284, rho = -.04), and abdominal aortic plaque (N = 1286, rho = -.06) did not correlate with MoCA Total Score (p ≥.048). Though MoCA scores were successively lower with increasing numbers of both direct atherosclerotic indicators [F(2, 633) = 1.40)] and indirect atherosclerotic indicators [F(2, 1048) = 1.09], the differences were not significant (p ≥ .248).The factors that most related to lower MoCA performance were race, gender, and education. There was no difference in MoCA Total Scores or measures of atherosclerosis between participants with an E4 allele and those without the E4 allele. There was no significant relationship between positive CAC, elevated abdominal AWT, and abdominal aortic plaque to MoCA scores obtained 7-8 years later. This relationship did not significantly increase with age and was not influenced by the presence of one or more apolipoprotein E4 alleles. This study does not support an association between direct or indirect measures of atherosclerosis in middle age and global cognition assessed 8 years later in this ethnically diverse population-based sample.Item Transcriptional Profiling of Early Cardiac Development(2005-08-11) Masino, Amanda M.; Garry, Daniel J.Cardiogenesis is an intricate process that spans nearly the entire developmental history of the mammal. A thorough comprehension of the molecular interactions that direct cardiac development will improve our ability to understand and treat cardiovascular diseases. The earliest stages of heart development are of particular interest because it is during these stages that patterning of cardiac structure appears critical. Traditionally, studies of these early developmental processes have been conducted on chicken, fish, or frog embryos due to ease of manipulation. More recently, however, the wide availability of tools designed to manipulate and isolate cell populations in the murine embryo, together with the advent of technologies for studying gene expression at the transcriptome level, have allowed for detailed study of these events in mammalian systems. I applied transgenic labeling and flow cytometry to isolate cardiac cell populations from early mouse embryos. Transcriptome analysis of these cell populations allowed me to characterize unique gene expression patterns and identify novel genetic pathways relevant to cardiac development. I undertook three interrelated studies. First, I completed a survey of the transcriptome of the developing heart at the cardiac crescent, linear heart tube, and looped heart tube stages to describe molecular signatures in the developing heart. I defined gene expression patterns unique to the cardiac crescent and looped heart, and identified novel markers of the developing heart. The second study focused on defining the transcriptional network of a key cardiac regulator, Nkx2.5. I identified transcripts misexpressed during the early development of Nkx2.5 null embryos, including the Nkx2.5 transcriptional targets ETSrelated transcription factor 71 and vascular cell adhesion molecule. Lastly, I characterized Nkx2.5-dependent left-right patterning in the cardiac crescent that revealed early specification of chamber myocardial lineages. In conclusion, these studies have elucidated the molecular profile of the developing heart and provided novel insights into the earliest stages of cardiac development.