Hypertension is considered as an important risk factor for the development of atherosclerosis, with these processes sharing some common mechanisms. The endothelium is placed usually as a probable central focus for the effects in both diseases, with evidences leading to the postulation that hypertension predispose and accelerate atherosclerosis. Coronary myocardial-disease is the main death cause in hypertensive patients.
Stress is one of the suggested factors for the hypertension origin and its reduction may help to reduce an elevated blood pressure. Coincidently stress can also contribute for the development and subsequent complications of atherosclerosis what is evidenced in many studies (1).
The key mechanism according the acidity theory of atherosclerosis (1) as the triggering factor for hypertension and atherosclerosis, is the elevation of the lactic acid production in blood. It is interesting to note that lactic acid in blood plasma can have a significant elevation during stress situations , serving as an indicator of stress levels (2, 3). Also, high carbohydrate diet may increase significantly the activity of serum lactate dehydrogenase (4,5). On the other side the concentration of lactic acid in both venous and arterial blood may be significantly elevated in hypertension as showed a study published 45 years ago (6), which results were confirmed recently by the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study, that measured plasma lactate in 2066 older adults. This study came to the conclusion that high plasma lactate was independently associated with the odds of hypertension (7).
1) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
2) Sharda S, Gupta SN and Khuteta KP. 1975. Effect on mental stress on intermediate carbohydrate-and lipid-metabolism. Indian J Physiol Pharmacol. Apr-Jun;19(2):86-9.
3) Hall JB, Brown DA. 1979. Plasma glucose and lactic acid alterations in response to a stressful exam. Biol Psychol. May;8(3):179-88.
4) Marshall MW and Iacono JM (1976). Changes in lactate dehydrogenase, LDH isoenzymes, lactate, and pyruvate as a result of feeding low fat diets to healthy men and women. Metabolism. 1976 Feb;25(2):169-78.
5)Yoshimura T, Miyoshi T, et al. (1986). Effect of high carbohydrate diet on serum lactate dehydrogenase isozyme pattern in Japanese young men. Acta Biol Hung. 1986;37(3-4):243-8.
6) F. E. Demartini, P. J. Cannon, W. B. Stason, and J. H. Laragh. 1965. Lactic Acid Metabolism in Hypertensive Patients. Science 11 June, Vol. 148. no. 3676, pp. 1482 – 1484 em http://www.sciencemag.org/cgi/content/abstract/148/3676/1482
7) Abstract 5003: Association of Blood Lactate with Hypertension: The Atherosclerosis Risk in Communities Carotid MRI Study. J Hunter Young; Stephen O Crawford; Frederick L Brancati; Ron C Hoogeveen; Muhammad Amer; Christie M Ballantyne; Maria I Schmidt; Brad C Astor; Josef Coresh, Circulation. 2008;118:S_1129.), http://circ.ahajournals.org/cgi/content/meeting_abstract/118/18_MeetingAbstracts/S_1129-a
Friday, November 27, 2009
The anti-atherosclerotic effects of cardiac glycosides
A recent study has showed that cardiac glycosides have anti-atherosclerotic effects (1). This was foreseen in the acidity theory of atherosclerosis, because these cardiotonics have properties of reduction of lactic acid concentration in blood and a specific sympathoinhibitory response by blocking the overproduction of catecholamine. (2). Also compatible with the acidity theory concept is the conclusion from the authors of the present study telling that low concentrations of digitoxin would help to avoid side effects and might represent a specific therapeutically option for the treatment of inflammatory cardiovascular disease, such as atherosclerosis.
1) Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis?, Joanna Jagielska, Gustavo Salguero, Bernhard Schieffer, Udo Bavendiek, doi:10.1016/j.atherosclerosis.2009.03.019
2) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
1) Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis?, Joanna Jagielska, Gustavo Salguero, Bernhard Schieffer, Udo Bavendiek, doi:10.1016/j.atherosclerosis.2009.03.019
2) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
The potential anti-atherosclerotic effects of proton pump inhibitors
A recent study has shown that calcium phosphate crystals of approximately 1 micron or less in diameter caused rapid rises in intracellular calcium concentration, an effect that was inhibited by the lysosomal proton pump inhibitor, bafilomycin A1 which also blocked vascular smooth muscle cell death. This suggested to the authors that calcium phosphate crystals are rapidly degraded in lysosomes and subsequent acidification leads to the release of calcium into the cell (1)
A study looking to demonstrate that when subintimal macrophages come into contact with LDL aggregates, an extracellular, acidic, hydrolytic compartment (a lysosomal synapse) is formed., with bafilomycin A1 blocking the free cholesterol production in this compartment (2)
Another study has discussed about the potential anti-atherosclerotic effects of proton pump inhibitors (3).
The above studies give great support to the acidity theory of atherosclerosis concept (4)
1) Calcium Phosphate Crystals Induce Cell Death in Human Vascular Smooth Muscle Cells: A Potential Mechanism in Atherosclerotic Plaque Destabilization, Alexandra E. Ewence et al, Circ. Res. 2008;103;e28-e34; at http://circres.ahajournals.org/cgi/content/full/103/5/e28
2) Macrophages Create an Acidic Extracellular Hydrolytic Compartment to Digest Aggregated Lipoproteins, Haka, A.S., I. Grosheva, E. Chiang, A.R. Buxbaum, B.A. Baird, L.M. Pierini and F.R. Maxfield. Mol. Biol. Cell, in press 2009, at http://www.molbiolcell.org/cgi/reprint/E09-07-0559v1
3) The potential anti-xanthoma and anti-atherosclerotic effects of proton pump inhibitors, M. R. Namazi, MD and M. Sharifian, MD. Journal of Clinical Pharmacy and Therapeutics (2008) 33, 579–580
4) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
A study looking to demonstrate that when subintimal macrophages come into contact with LDL aggregates, an extracellular, acidic, hydrolytic compartment (a lysosomal synapse) is formed., with bafilomycin A1 blocking the free cholesterol production in this compartment (2)
Another study has discussed about the potential anti-atherosclerotic effects of proton pump inhibitors (3).
The above studies give great support to the acidity theory of atherosclerosis concept (4)
1) Calcium Phosphate Crystals Induce Cell Death in Human Vascular Smooth Muscle Cells: A Potential Mechanism in Atherosclerotic Plaque Destabilization, Alexandra E. Ewence et al, Circ. Res. 2008;103;e28-e34; at http://circres.ahajournals.org/cgi/content/full/103/5/e28
2) Macrophages Create an Acidic Extracellular Hydrolytic Compartment to Digest Aggregated Lipoproteins, Haka, A.S., I. Grosheva, E. Chiang, A.R. Buxbaum, B.A. Baird, L.M. Pierini and F.R. Maxfield. Mol. Biol. Cell, in press 2009, at http://www.molbiolcell.org/cgi/reprint/E09-07-0559v1
3) The potential anti-xanthoma and anti-atherosclerotic effects of proton pump inhibitors, M. R. Namazi, MD and M. Sharifian, MD. Journal of Clinical Pharmacy and Therapeutics (2008) 33, 579–580
4) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
LDL oxidation occurs within lysosomes in cells
Recent evidence showed that LDL oxidation occurs not within the interstitial fluid of atherosclerotic lesions but within lysosomes in macrophages in atherosclerotic lesions. Most important, the study found that this oxidative modification was inhibited by the drug chloroquine, which increases the pH of lysosomes, as oxidation can be promoted by acidic pH (1, 2)
1) Low Density Lipoprotein Undergoes Oxidation Within Lysosomes in Cells, Yichuan Wen and David S. Leake, Circ. Res. 2007;100;1337-1343; em http://circres.ahajournals.org/cgi/content/full/100/9/1337
2) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
1) Low Density Lipoprotein Undergoes Oxidation Within Lysosomes in Cells, Yichuan Wen and David S. Leake, Circ. Res. 2007;100;1337-1343; em http://circres.ahajournals.org/cgi/content/full/100/9/1337
2) Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at http://www.infarctcombat.org/AcidityTheory.pdf
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