Lecture 9 AI generated Flashcards

1
Q

Describe ischemic heart disease.

A

Ischemic heart disease, also known as cardiac ischemia, is a condition where there is insufficient blood flow to the heart tissue, leading to tissue injury due to ATP depletion. The duration of ischemia determines the severity of the damage, with longer durations resulting in more severe consequences.

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2
Q

What is reperfusion in the context of ischemic heart disease?

A

Reperfusion is the restoration of blood flow to the affected tissue after a period of ischemia. While reperfusion is necessary to limit damage, it can also contribute significantly to tissue injury.

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3
Q

Define oxidative stress in the context of ischemia/reperfusion.

A

Oxidative stress refers to an imbalance between the production of reactive oxygen species (ROS) and the ability of the body to detoxify them. In the case of ischemia/reperfusion, excessive ROS generation can lead to damage in the heart tissue.

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4
Q

How can people with ischemia be treated with cardiac reperfusion?

A

People with ischemia can be treated with cardiac reperfusion through procedures like percutaneous coronary intervention (PCI), which aims to restore blood flow to the heart tissue.

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5
Q

Describe the role of reactive oxygen species (ROS) in ischemia/reperfusion.

A

ROS, which are reactive oxygen species or radicals of oxygen, have an important physiological signaling function, but excessive ROS production can lead to oxidative stress and damage in the heart tissue during ischemia/reperfusion.

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6
Q

What are some of the consequences of exposure to ROS in animals during ischemia/reperfusion?

A

Exposure to ROS in animals during ischemia/reperfusion can lead to deletion of superoxide dismutase (SOD), overexpression of ROS generating enzymes, and the presence of ROS footprints like lipid peroxidation, oxidized glutathione (GSSG), and fluorescent probes.

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7
Q

Describe the role of mitochondria in producing reactive oxygen species (ROS).

A

Mitochondria are a significant source of ROS, which can lead to damage to DNA, lipids, and membranes.

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8
Q

What is the impact of ROS on the heart during ischemia reperfusion?

A

ROS can cause oxidative damage, leading to an increase in infarct size. Counteracting this process, such as with vitamin C treatment, can reduce infarct size.

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9
Q

Define oxidative phosphorylation and its relation to ROS production.

A

Oxidative phosphorylation is a process in the mitochondria that can lead to the production of ROS, which can be mitigated by enzymes like ETC and NNT.

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10
Q

How does the type of fuel used by the heart change in diseased conditions?

A

In diseased conditions, the heart switches from primarily using fat for energy to relying more on sugar as a fuel source.

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11
Q

Describe the therapeutic implications of reducing ROS damage during acute myocardial infarction.

A

Reducing ROS damage, such as through vitamin C treatment, can potentially decrease infarct size by up to 50%.

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12
Q

What are some factors that can influence the effectiveness of ROS-targeted therapies?

A

Factors such as dosage, diet, administration method (intravenous/oral), and individual variations in ROS production can impact the effectiveness of ROS-targeted therapies.

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13
Q

Describe the role of HIF-1 in response to ischemia/hypoxia.

A

HIF-1 is a transcription factor that regulates the response to low oxygen levels. It promotes survival, restores oxygen delivery, and regulates processes like metabolic adaptation, cell survival, redox homeostasis, and angiogenesis.

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14
Q

What are the key roles of HIF-1 in cellular processes?

A

The key roles of HIF-1 include metabolic adaptation (especially glucose metabolism), cell survival, redox homeostasis, and angiogenesis.

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15
Q

How does HIF-1 mediate metabolic adaptations under hypoxic conditions?

A

HIF-1 promotes the use of carbohydrates as a fuel source instead of fat in the heart during ischemia, helping in reducing damage and the risk of a myocardial infarction.

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16
Q

Define HIF-1 alpha and its function in gene regulation.

A

HIF-1 alpha is the regulated component of the HIF-1 transcription factor. It recognizes genes with a hypoxia response element (HRE) and, with co-activators, transcribes genes involved in metabolic adaptation, cell survival, ROS detoxification, and angiogenesis.

17
Q

What happens in HIF1-alpha deficiency in humans and mice?

A

HIF1-alpha deficiency in humans is associated with congenital heart defects. In mice, Hif1a knockout leads to embryonic death at day 10.5 due to cardiac and vascular defects, decreased red blood cell production, and circulatory system abnormalities.

18
Q

Can you explain the role of ROS detoxification in the context of HIF-1 regulation?

A

HIF-1 regulates genes involved in ROS detoxification, helping in maintaining redox homeostasis and protecting cells from oxidative damage during hypoxic conditions.

19
Q

Describe the process of HIF1A degradation under normoxia conditions.

A

Under normoxia, hydroxylated HIF1A cannot bind cofactors, dimerize, or escape VHL binding, leading to ubiquitination and proteasomal degradation.

20
Q

What happens to HIF1A under hypoxia conditions?

A

Under hypoxia, HIF1A is not hydroxylated, allowing it to enter the nucleus, dimerize with ARNT, and initiate transcription with cofactors EP300/CREBBP.

21
Q

Define the role of EGLNs and HIF1AN in regulating HIF1A.

A

EGLNs and HIF1AN hydroxylate HIF1A, a process dependent on oxygen, Fe2+, 2-oxoglutarate, and ascorbate, leading to its degradation under normoxia.

22
Q

How do various factors inhibit EGLNs and HIF1AN?

A

Factors like lack of oxygen, reactive oxygen species, fumarate, succinate, iron chelators, and Co2+ inhibit EGLNs and HIF1AN, affecting the hydroxylation of HIF1A.

23
Q

Describe the critical dependence of EGLNs and HIF1AN function on specific elements.

A

The function of EGLNs and HIF1AN is critically dependent on oxygen, Fe2+, 2-oxoglutarate (αKG), and ascorbate for the hydroxylation of HIF1A.