Exercise and vascular function in sedentary lifestyles in humans, 2023, Fasipe et al.

SNT Gatchaman · Jul 15, 2023

Exercise and vascular function in sedentary lifestyles in humans
Fasipe, Babatunde; Li, Shunchang; Laher, Ismail

People with sedentary lifestyles engage in minimal or no physical activity. A sedentary lifestyle promotes dysregulation of cellular redox balance, diminishes mitochondrial function, and increases NADPH oxidase activity. These changes collectively increase cellular oxidative stress, which alters endothelial function by oxidizing LDL-C, reducing NO production, and causing eNOS uncoupling. Reduced levels of nitric oxide (NO) leads to vasoconstriction, vascular remodeling, and vascular inflammation. Exercise modulates reactive oxygen species (ROS) to modify NRF2-KEAP signaling, leading to the activation of NRF2 to alleviate oxidative stress. While regular moderate exercise activates NRF2 through ROS production, high-intensity intermittent exercise stimulates NRF2 activation to a greater degree by reducing KEAP levels, which can be more beneficial for sedentary individuals. We review the damaging effects of a sedentary lifestyle on the vascular system and the health benefits of regular and intermittent exercise.

Link (Pflügers Archiv - European Journal of Physiology) Paywall

SNT Gatchaman · Jul 15, 2023

The adverse effect of a sedentary lifestyle is linked to two important factors, namely increases in oxidative stress and LDL-C levels. Increased physical activity reduces oxidative stress by enhancing the antioxidant system through NRF2 activation and reducing oxidized LDL-C in inactive subjects, which are both beneficial to patients with sedentary lifestyles.
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While moderate-intensity exercise (40% to 59% functional capacity) and vigorous exercise (60% or more of functional capacity) for about 35 min/day seem to provide maximal benefits. Exhaustive and vigorous exercise has been associated with accelerated coronary artery calcification, elevated cardiac biomarker release, myocardial fibrosis, atrial fibrillation, and hypertrophic cardiomyopathy. These effects are related to excessive ROS production, which overcomes the effect of protective antioxidants initially activated by moderate exercise, leading to oxidative stress-related tissue damage and cardiovascular events.
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It is counterintuitive that exercise capable of increasing ROS is beneficial for people with a sedentary lifestyle where ROS is responsible for most of the deleterious effects of an inactive lifestyle. Important in this context is that high levels of ROS with short duration released during exercise lead to NRF2 activation, which controls the transcription of more than 200 antioxidant genes to mediate cardiovascular protection. However, the concentrations of ROS produced in the endothelial cells of people with a sedentary lifestyle can cause damage without stimulating the NRF2 pathway. In addition, NRF2 improves mitophagy which removes damaged proteins/organelles to protect the integrity of the endothelium.
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The main mechanism involved in oxidative stress is the disruption of the electron transport chain by the release of cytochrome-c oxidase which inhibits oxidative phosphorylation. Dynamin-related protein 1 (DRP1) is a stress-induced enzyme that is regulated by the oxidative state of the cell and is involved in controlling mitochondrial fission and cytochrome-c oxidase release. Controlling activation through regulation of DRP1 phosphorylation can be achieved by NRF2 stimulation. Suppression of DRP1 prevents cytochrome-c release and increases ROS production. Exercise stabilizes DRP1 through NRF2 activation. Sulforaphane, an NRF2 activator, prevents mitochondrial dysfunction and oxidative damage through the stabilization of DRP1
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SNT Gatchaman · Jul 15, 2023

Catch-22.

SNT Gatchaman · Jul 16, 2023

There are a few wording and graphical errors but I think this is an interesting paper.

If it's true that reduced NO bioavailability leading to endothelial dysfunction is a significant part of our pathophysiology, then a vicious cycle of inability to exercise may reinforce that process. However, this paper has some suggestions for alternative strategies in people who can't exercise, eg morbid obesity and spinal cord injury. This could therefore be relevant to us.

I'll post a few more snippets over the day, but first some of the references they use that are open-access.

SNT Gatchaman · Jul 16, 2023

Some open access refs —

ROS / Oxidate Stress
Endothelial Function and Oxidative Stress in Cardiovascular Diseases (2009, Circulation Journal)
Physical Inactivity Increases Oxidative Stress, Endothelial Dysfunction, and Atherosclerosis (2005, Arteriosclerosis, Thrombosis, and Vascular Biology)
Endothelial Dysfunction in Cardiovascular Diseases: The Role of Oxidant Stress (2000, Circulation Research)

Nitric Oxide / eNOS
Endothelial function and nitric oxide: clinical relevance (2001, Heart)

Oxidised LDL
Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis (2022, Frontiers in Cardiovascular Medicine)

BH4 / Peroxynitrite
Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS (2008, American Journal of Physiology-Heart and Circulatory Physiology)
Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite (2002, The Journal of Clinical Investigation)
Endothelial Regulation of Vasomotion in ApoE-Deficient Mice (2001, Circulation)

Rescue of endothelial dysfunction with exercise
Sitting and endothelial dysfunction: The role of shear stress (2012, Medical Science Monitor)

Rescue of endothelial dysfunction without exercise
Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway (2020, Cardiorenal Medicine)
Activation of transcription factor Nrf2 to counteract mitochondrial dysfunction in Parkinson's disease (2021, Medicinal Research Reviews)
The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state (2016, Nutrition Journal)

SNT Gatchaman · Jul 16, 2023

Some of the paywalled references, with cache links where available —

High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response (2021, Free Radical Biology and Medicine)
Dual Role of Mitophagy in Cardiovascular Diseases (2021, Journal of Cardiovascular Pharmacology)
Berberine protects Kawasaki disease-induced human coronary artery endothelial cells dysfunction by inhibiting of oxidative and endoplasmic reticulum stress (2020, Vascular Pharmacology, cached)
FNDC5 inhibits foam cell formation and monocyte adhesion in vascular smooth muscle cells via suppressing NFκB-mediated NLRP3 upregulation (2019, Vascular Pharmacology, cached)

Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction (2017, International Journal of Cardiology, cached)
MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA (2017, Molecular Immunology, cached)
Exercise Mimetics: Running Without a Road Map (2017, Clinical Pharmacology & Therapeutics, cached)
Ginsenoside Rg3 antagonizes adriamycin-induced cardiotoxicity by improving endothelial dysfunction from oxidative stress via upregulating the Nrf2-ARE pathway through the activation of akt (2015, Phytomedicine, cached)

Modulation of oxidative stress as an anticancer strategy (2013, Nature Reviews Drug Discovery, cached)
Dihydrofolate reductase and biopterin recycling in cardiovascular disease (2009, Journal of Molecular and Cellular Cardiology, cached)
The role of inflammatory cytokines in endothelial dysfunction (2008, Basic Research in Cardiology, cached)
Role of oxidative stress in atherosclerosis (2003, American Journal of Cardiology)
Atherosclerosis — An Inflammatory Disease (1999, New England Journal of Medicine)

SNT Gatchaman · Jul 16, 2023

The danger created by oxidative stress lies in the reactivity of ROS with other cellular components such as DNA, proteins, carbohydrates, and lipids, limiting their functions as in the case of the endothelium.
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Apart from the mitochondria which are the main sources of ROS, other sources of ROS include enzymatic systems such as NADPH oxidase (NOX), xanthine oxidase (XO), cyclooxygenase (COX) and uncoupling of eNOS, but most studies on sedentary patients have focused on mitochondrial dysfunction, NADPH oxidase (NOX) activation, and uncoupled eNOS as a source of excessive ROS leading to oxidative stress.
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Increases in oxidative stress, brought about by excessive ROS production coupled with inadequate functioning of the endogenous antioxidant systems, is one of the primary causes of endothelial dysfunction. The consequence of a compromised endothelium function is the reduction in NO availability [...] One of the main protective chemicals in the endothelial system is NO.
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The precursor in the synthesis of NO is L-arginine, which combines with, molecular oxygen, NADPH, tetrahydrobiopterin, flavin adenine dinucleotide, and flavin mononucleotide with the help of the enzyme endothelial nitric oxide synthase (eNOS) to synthesize NO.
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Chemical endothelial agonists such as acetylcholine (ACh), substance P, bradykinin, and physical agonist such as elevated shear stress activate eNOS, leading to increases in NO production. Inactivity in mice on the other hand increases vascular lipid peroxidation to levels that are almost double that of active mice, due to increased oxidative stress, which causes a reduction in NO synthesis.
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SNT Gatchaman · Jul 16, 2023

Physical inactivity prevents NRF2 activation which increases oxidative stress to aggravate ROS production and mitochondrial dysfunction. Damage imposed on mitochondrial DNA can escalate oxidative stress and increase the activation of proteins, such as DRP1, that can disrupt the electron transport chain by the release of cytochrome-c oxidase. Therefore, diminished mitochondrial function experienced in a sedentary lifestyle is related to increases in oxidative mechanisms mediated through a dysfunctional electron transport chain.
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The bioavailability of NO is an important determinant of vascular health, with the synthesis of NO being affected by the oxidative state of the cell and also by exercise, which reduces oxidative stress levels to enhance NO production. NOX activation upgrades endothelial production of ROS, which oxidizes the cofactor tetrahydrobiopterin (BH4) which is a pre-requisite for NO production. BH4 enhances the formation eNOS dimers (the active form) from monomers, while a decrease in BH 4 leads to the ineffective transfer of electrons to eNOS.
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Peroxynitrite, a product of a reaction of NO and ROS, interacts with endothelial cells uncoupling eNOS dimers. Peroxynitrite and other ROS oxidize BH 4 to BH2 in vivo, and BH 2 competes with BH4 for eNOS as they bind to the same domain on eNOS. BH2, therefore, acts as an antagonist or a suppressor of eNOS activity, so that under conditions of oxidative stress, NO production is compromised by the increased production of peroxynitrite.
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Higher metabolic rates in endothelial cells can make them more prone to oxidative stress and metabolic dysfunction.
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The pathway to endothelial dysfunction through oxidative stress is mainly mediated by the oxidation of low density lipoprotein cholesterol (LDL-C). High levels of oxidized LDL-C leads to accumulation in macrophages in the form of foam cells. [...] Oxidized LDL-C can also promote the formation of lysophosphatidylcholine which causes a concentration-dependent decline in the eNOS resulting in a low bioavailability of NO.
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SNT Gatchaman · Jul 16, 2023

The adverse effect of a sedentary lifestyle is linked to two important factors, namely increases in oxidative stress and LDL-C levels. Increased physical activity reduces oxidative stress by enhancing the antioxidant system through NRF2 activation and reducing oxidized LDL-C in inactive subjects
Click to expand...

A current study has revealed that high-intensity exercise can elicit greater adaptive responses through the downregulation of KEAP1, making it more beneficial than moderate exercise which relies mainly on ROS for NRF2 activation.
Click to expand...

It is counterintuitive that exercise capable of increasing ROS is beneficial for people with a sedentary lifestyle where ROS is responsible for most of the deleterious effects of an inactive lifestyle. Important in this context is that high levels of ROS with short duration released during exercise lead to NRF2 activation, which controls the transcription of more than 200 antioxidant genes to mediate cardiovascular protection.
Click to expand...

However, the concentrations of ROS produced in the endothelial cells of people with a sedentary lifestyle can cause damage without stimulating the NRF2 pathway.
Click to expand...

SNT Gatchaman · Jul 16, 2023

Possibilities for mitigating endothelial dysfunction —

Their emphasis said:

MOTS-c is a mitochondrial-derived peptide that is induced by exercise and which enhances metabolic homeostasis. Aerobic exercise (4–8 weeks) increases MOTS-c protein expression by 1.5–fivefold and the beneficial effects are sustained for 4–6 weeks after detraining in rats. These and other findings have prompted MOTS-c to be regarded as an "exercise mimic with actions similar to aerobic exercise”.
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Reduced activation of mitochondrial MOTS-c in humans is closely related to an endothelial malfunction. The mechanism involved in endothelial dysfunction includes the activation of nuclear factor-κB (NF-κB), which controls several pro-inflammatory chemokines. MOTS-c can suppress the expression of pro-inflammatory cytokines such as IL-6 and TNF-α, which by inhibiting MAPK signaling, initiates the downstream transcription of the pro-inflammatory protein NF-κB.
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The ability of MOTS-c to improve endothelial dysfunction suggests that it may be a promising treatment for people with endothelial dysfunction induced by sedentary lifestyles.
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The main mechanism involved in oxidative stress is the disruption of the electron transport chain by the release of cytochrome-c oxidase which inhibits oxidative phosphorylation. Dynamin-related protein 1 (DRP1) is a stress-induced enzyme that is regulated by the oxidative state of the cell and is involved in controlling mitochondrial fission and cytochrome-c oxidase release. Controlling activation through regulation of DRP1 phosphorylation can be achieved by NRF2 stimulation. Suppression of DRP1 prevents cytochrome-c release and increases ROS production. Exercise stabilizes DRP1 through NRF2 activation. Sulforaphane, an NRF2 activator, prevents mitochondrial dysfunction and oxidative damage through the stabilization of DRP1.
Click to expand...

While exercise is known to activate NRF2, not everyone can engage in the necessary level of physical activity. For individuals with spinal cord injury, paraplegia, or morbid obesity, pharmacological approaches that mimic the beneficial effect of exercise could be beneficial. Most pharmacological NRF2 activators work by covalently modifying cysteine residue in the KEAP1 protein through oxidation. Examples of NRF2 activators include compounds such as sulforaphane, bardoxolone, curcumin, and resveratrol.
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Sean · Jul 16, 2023

While exercise is known to activate NRF2, not everyone can engage in the necessary level of physical activity.

This is an important acknowledgement.

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Exercise and vascular function in sedentary lifestyles in humans, 2023, Fasipe et al.

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