Sunday, October 7, 2012

Endothelial Dysfunction

Endothelial Dysfunction

Endothelial cells secrete substances to maintain an appropriate degree of clotting, cell proliferation, blood pressure, etc.  Perhaps the most important of these substances is nitric oxide (NO), which inhibits LDL oxidation and is a vasodilator (relaxes the blood vessels to lower blood pressure).  A defect in the production or activity of NO leads to endothelial dysfunction (ED) [1] [2]. 

ED leads to an increase of endothelial permeability, LDL oxidation, platelet aggregation, leukocyte adhesion, pro-inflammatory cytokines, vasoconstriction and smooth muscle cell proliferation – all of which are factors that promote atherosclerosis to varying degrees [2].  Evidence to support the role of ED in atherosclerosis:

  • ED is a strong independent predictor of CVD [3].  In a sample of 157, those with mild ED and without ED had no cardiac events, while 6 people (14%) with severe ED had cardiac events after 28 months [4]
  • People with CVD tend to have ED, and atherosclerosis and hypertension strongly predict ED [5]
  • Correcting ED through several means (arginine (precursor to NO), statins and increasing NO availability/activity) improves cardiac outcomes [4]


ROS and reactive nitrogen species (RNS) are a cause of endothelial dysfunction [1].  In particular superoxide (O2-) can combine with nitric oxide (NO) to form peroxynitrite (ONO2).  This process generates a more powerful oxidant and displaces NO.  Peroxynitrite (PON) is a 2e oxidant and has a number of effects that promote CVD:

  • PON nitrates prostacyclin synthase, which decreases prostacyclin, an eicosanoid derived from arachidonic acid that is anti-inflammatory, a vasodilator and inhibits blood clotting [1]
  • PON can modify LDL and PON modified LDL has a high affinity for macrophage scavenger receptors [1]
  • PON inhibits mtSOD and the electron transport chain, which leads to more superoxide and more PON [1]
  • PON upregulates adhesion molecules in endothelial cells and neutrophil adhesion [1]
  • PON uncouples NO synthase which leads to the production of superoxide rather than NO [1]
  • PON triggers apoptosis in endothelial and smooth muscle cells [1]
  • PON promotes mitochondrial dysfunction [6]

Mitochondrial Dysfunction

Mitochondria are the energy factories of the cell, but in the process of processing energy mitochondria also produce reactive oxygen species (ROS).  If the ROS are not dealt with by antioxidant defenses, then they are free to cause oxidative stress.  Mitochondria and their DNA (mtDNA) are most vulnerable due to their close proximity.  ROS inhibit ATP production and can damage mtDNA, leading to mutations.  This initiates a positive feedback cycle whereby mutations in mtDNA compromise mitochondrial function, slow down the electron transport chain and lead to more ROS, more oxidative stress and more mutations. 

Mitochondrial dysfunction is a condition of low energy production, high oxidative stress, elevated pro-inflammatory cytokines, pro-apoptotic signaling, insulin resistance, etc.  Mitochondria produces 90% of the endogenous ROS [7], which begins as superoxide and can combine with NO to form PON and lead to ED.  Insulin resistance can lead to hyperglycemia and increased free fatty acids, which further increases superoxide generation in the mitochondria [8] [9].  Evidence supporting the role of mitochondrial dysfunction in CVD:

  • Hearts from patients with CAD had 8-2000 times more mtDNA deletions than controls [8]
  • Blood vessels often have inefficient ATP production before developing atherosclerosis [10]
  • Mitochondrial dysfunction precedes atherosclerosis in animal models of atherosclerosis [11]
  • There is more mtDNA damage in the blood vessels of people with atherosclerosis and mtDNA mutations correlate with atherosclerosis [11]
  • Age is one of the strongest risk factors for CVD and mitochondrial dysfunction is a major contributor to the aging process.  mtDNA mutations accumulate with age and are inversely correlated with maximal life span [8]
  • People with LDL >130mg/dl tend to have more mtDNA mutations and more oxidative stress [12]
  • Mitochondrial superoxide promotes atherosclerosis and mtSOD is protective against atherosclerosis [6]
  • Mitochondrial superoxide has been found to be required to oxidise LDL in vitro [13]
  • Atherosclerotic lesions in Alzheimer’s have increased mtDNA deletions [8]
  • Mitochondrial dysfunction is an important link between CVD with obesity [14] and the metabolic syndrome [15] 

* After 1 year, CoQ10 and statins reduced cardiac events in patients who previously had an MI  by 45.3% compared with B Vitamins and statins.  Also, the CoQ10 group had only one sixth of the side effects (fatigue) from statins [16]

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