The Vast Need of The Human Carriage and Why Synthetic Vitamins, Especially Synthetic Vitamin C Is Necessary.

Everybody needs to run away from romantic delusions of two sorts.

One the pathetic crypto-Nazi sentiment that they or a population of humanity does not need as much Vitamin C.  Given that the predicted human lifespan should easily be 150 years with vigor and youth retained at age 100, this is a laughable retrospective delusion.  There is not a person on Earth who doesn't need to rescue their genetic defect in their L-Gulono-y-lactone oxidase gene.  Nordic, Germanic, whatever.  It doesn't include you either.  You still need multi-gram quantities of ascorbate through your entire life without cessation.

The other, a naturalist idea, that we must succumb to our biological frailties because we are supposed to have them.  Then there is no point to medical science and progress.  It is akin to a sort of suicide, philosophical at its core, but in action a suicide.  Science is intrinsically artificial and synthetic.  Not everything of nature is good for humans.  The loss of Vitamin C synthesis, for example, was intended to cripple humanity.  Natural and Synthetic are not synonymous with "Good" and "Bad."  We must wipe this illogical association from our minds.  A Toshiba computer is what?  Natural??

We are obliged to respect and preserve The Earth and its pristine ecologies, unpoisoned by Man, but this may also take technology to do so.

The premise is and always will be that several grams of ascorbate a day are necessary to prevent and treat human cardiovascular diseases.  It is not the only element necessary.  The human physiology is vastly needy with many biochemical auxotrophies crippling it, not just the Gulo gene absence.  If we were replete with these substances, we would be like plants, just needing mineral water, sunshine, and carbon dioxide.  We're not plants.  Humans take tremendous and vast resources to support on a physiological level, but we wouldn't be the most resource intensive mammal.  Certain whales take enormous food resources.

Why pretend we don't need exactly what we need?  Knowing that say 4 grams of ascorbate is what all humans need minimally per day to stall or prevent heart attacks and strokes, that would mean the equivalent of Vitamin C contained in 40 oranges...a day.  Is it practical to rely on orange tree or lemon tree orchards to prevent heart disease and cancer?  To cut to the chase, NO.  Not for us, a mammal that has been GENETICALLY HANDICAPPED.  All humans possess this defect, so no proud want-to-be Nazi can gloat that they need less Vitamin C than their "lesser" peer.

Let's break it down in real-life terms and show why it is exactly about "vitamin pills."  You cannot rely on vitamin pill sales and then claim that it "isn't about vitamin pills."  Without the commerce element, it is ever about vitamin pills to save the human race from suffering.

Orange Orchard Logistics 101 - You need to learn this before making some stupid, embarrassing global claim about planting oranges everywhere.

In a "high density" orchard, consisting of one acre, nevermind water requirement, there are 1500 orange trees.  Each will produce 300 oranges per tree at year 5, for a total of 450,000 oranges per year on one acre.  Remember, this is land that is dedicated to orange and nothing and nobody else.  Minus the juice, that is 45,000 grams of ascorbate per year.  It seems like a great deal, but let's break it down further given real world parameters.  Given ALL adults require MINIMALLY 4 grams a day, everyday for prevention of major disease, this breaks down to 45,000/4grams a day/365 days a year = Less than 31 people.

This is less than needed to keep 31 people healthy. 

The population of Europe was 742,500,000 people in 2013.  In order to indirectly and inefficiently make 4 grams of Vitamin C for all these individuals per year, you would need a citrus orchard of 23,951,612 acres size.  This translates to 37,500 square miles of orchard or greater than the size of Wisconsin.

Given that this is feasible, and certainly there are that many orange orchards, why hasn't orange juice saved humanity from atherosclerosis?  

There are about 8 oranges in a big 16 oz cup of juice, or two glasses of juice.  This would be 800 mg of Vitamin C, a good beneficial dose, but hardly enough to get to the therapeutic amount of 40 oranges a day, or 5 big glasses of orange juice (plus the sugars) EVERYDAY.  Not only does nobody do this, it is not tolerable.  As delicious as it is, nobody can stomach such enormous quantities of orange juice.  Attempting to EAT 40 oranges EVERYDAY is even worse.  If you are talking apples, we're talking ten times more apples - FOUR HUNDRED APPLES A DAY = 3.4 grams Vitamin C.

Only a concentrated extract taken undiluted would be and could be effective, and this would take...SCIENCE AND TECHNOLOGY to squeeze the nutrition of 400 apples into a tolerable volume!  It is deceptive and irresponsible to suggest that eating an orange or an apple a day will stave off the genetic defect all humans possess in some kind of romantic naturalism statement on behalf of somebody who does not take their vitamins, like a child who won't eat their vegetables.  There is an easier solution in place, synthetic but good and pure Vitamin C, also a product of science.  Naturalism, the human notion, is not always constructive or forward looking.  It can plunge you backwards to square one. 






 

Atherosclerosis Is Not A Modern Disease. Lifespan Was Shorter Not Longer In Ancient Humans.

Looking at atherosclerotic plaque in people 4000 years ago.

Today we are awash with paleo diet recommendations or vegetarian/granarian/fruitarian diets, all consumed by ancient human beings.  They DIDN'T live longer, they lived much shorter lives.  People never reached 50 years of age, and this age was correlated with rampant atherosclerosis (plaque).  They certainly had orange and apple trees back then.  There is no shortage of apples in Europe, so that is clearly not the cause of atherosclerosis in Europe.  It is not because of an "apple tree deficiency."  Our clean eating ancestors had severe atherosclerosis before the age of 40.  Why could this be?  They ate plenty of apples...

The German and Norse Pagan festivals featured many many apples (to eat). "Brita as Iduna" (1901) by Carl Larsson:

We have a heritable in-born genetic defect of ascorbate synthesis that goes beyond just a sprinkle or dash.  It was the great pioneers such as Pauling, Stone, Cameron, Willis, who initiated the idea of megadose ascorbate consumption (which is not mega but actually normal).  The schizophrenic contradiction of wanting this threshold rescue dose of this genetic defect to be lower by the day is pure insanity.  It is like saying one day humans will not need to drink several glasses of water a day to be alive.  It "ain't gonna happen."  The orange tree idea takes us to square one, as the therapeutic dose for atherosclerosis is minimally 4,000 mg ascorbate.  That is 40 oranges, more than a tree may make all year.   Until the day we as a species actually genetically engineer back a working copy (is this natural?) to replace our corrupted yet present Gulo gene, we will need to take in effective amounts of the rescue substance, ascorbate.

That is the whole idea behind science, the mastery of our biological weaknesses, and so called "vitamins."  If we are naturalists to the extreme, throw away your computer, wear burlap sacks, live like a Quaker and we can forget about vitamin pills altogether, plunging ourselves all the way back to 4000 years ago where people were rife with atherosclerosis and lived to a little over 40 years of age despite "perfect" natural diets with no fried or packaged foods.

It's the missing substances, stupid.

Lipoprotein(a) and macrophages in tandem within a human coronary plaque biopsy:

Here are some pictures of Lp(a) together with macrophages taken from a human coronary atherosclerotic plaque.  Panel C are the macrophage foam cells, Panel D is Lp(a).  They are clearly one on top of the other.

This is taken from: Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation  from all the way back in 1998.  It would be inaccurate to say that there is only 1 person on the planet who recognizes Lp(a) as an atherogenic factor.

The question of causality and time-frame is always to question.  The essential point we're trying to make is that Lp(a) doesn't just swoop in from out of nowhere for no reason all the sudden.  Macrophages which do home into inflammatory cytokine signals emitted by the artery, and do burrow in to receive cholesterol via active receptor exchange to return to the liver, also don't just suddenly go in and start chewing up lipoproteins.  That being said, foam cells and Lp(a) happen together frequently.  In any remodeling process in the body, there is nearly certainly found macrophages.  You can't just ignore the immune system.

What is my position?  It is irrelevant.  It is beyond irrelevant "who is right," but what is germaine is "WHAT is right."  I do not care "who" is right, nor should you.  Those who care intensely about who should be right obviously have something else driving them like a jerk's ego or some frivolous vendetta.  The question should be, how do we make each and every one of the millions of people of Earth right in their application of science.  What we should all care about is "what is right," not "who is right."  Needless to say, that is my concern in science, no extraneous nonsense.

What is true is that macrophages are initially participating in a beneficial remodeling process, and not chewing up ox-LDL in some parasitic process, but attempting to hand back the remodeling waste, the construction site debris back to the liver for recycling via....HDL.  We certainly can't ignore HDL in this repair process either.  It will spin cardiopathology's noodle when they see that the majority of atherosclerotic plaques are rich in ApoE, which if extended the old logic applied to LDL is causing harmful things.  On the contrary, the presence of ApoE we all know to be part of the repair process which may be overwhelmed by a net excess of damage as opposed to a net excess of repair.

Does Lp(a) cause atherosclerosis?  Only if there is a reason for atherosclerosis to take place.  For a many humans who eat just an orange a day but still have the Gulo-/- genetic defect, there is a lot of cumulative damage that does occur which needs patching by Lp(a) and the coagulation system.  Think of it this way, when thinking about preserving arterial integrity: a normal rat makes the equivalent of 5 grams a day in a 70 kilo human when nothing is going on.  In stressful times, a rat makes 300% more vitamin C.  This entry certainly is not encouraging or supporting the fallacy that dietary cholesterol causes heart disease.  It does not, but other dietary factors such as too low vitamin C, B, E, magnesium, K, D, amino acids and too much trans-fatty acids and omega-6 do.  The recent US Federal guidance to stop paying attention to ingested cholesterol is a well-studied one made with decades of clinical evidence that cholesterol consumption has historically had nothing to do with the rate of heart disease.

I think this statement I made a long time ago sums it up nicely about what is going on:

 "A big lump is better than a big hole."

One prevents lethal hemorrhage, the most dramatic example in human biology being the aortic dissection with adventitial failure, the other is lethal hemorrhage.  One of the first priorities of the human physiology is to stop bleeding and hemorrhaging.  It drops everything it is doing and attends to that first, even if it means making a pile of disorganized stuff at the site of leaking that is harmful down the road.  Better than bleeding to death.  Lp(a) is very atherogenic at sites of arterial damage, and sticks more to the glycocalyx with ascending concentrations.  If the endothelium is in tact, there is nothing for Lp(a) to react to, no ligand, no binding site to the ligand.  Lp(a) just floats along harmlessly as it does not encounter plasminogen binding sites, free lysyls, fibrin, exposed subendothelial fibronectin, etc.  You can't just ignore the coagulation system either.  Lp(a) has a direct affinity to fibrin(ogen) which is Clotting Factor 1, and gets cross-linked to fibrin clots via FactorXIII.  Do macrophages foam cells CAUSE atherosclerosis?  No.  They are attempting to prevent it, but the process can and does go wrong if they get overwhelmed.  When they are participating in arterial repair, foam cells are formally defined as early plaques, but that is simply a matter of scientific semantics.  Perhaps one day, they will be relabeled as "reparative cells" distinct from a fibrofatty mass devoid of cells that can rupture and cause thrombosis. Given an equal sized foam cell lesion and fibrofatty mass with thin cap that is  less than 20% occlusive, the unstable fibrofatty mass is the dangerous thing, and the foam cell lesion is unconcerning.

Macrophages and foam cells are not always in human atherosclerotic plaques.  In fact, many times, they are not there at all.  Many pathologist specimens of human diseased atherosclerotic arteries do not have foam cells, which is why some scientists choose to de-emphasize them or diminish their importance.  But they do happen, and we can't just ignore them.  One improvement in the future state-of-the-art may be to put macrophages and foam cell "lesions" in a category all on their own as they are dynamically different from all other component atherosclerotic plaques, and not just different in cellular origin and composition.  They also serve an entirely different purpose altogether than other cells found in human plaques, including remodeling, debris clearance, and returning the artery back to its original state.

You can't just ignore foam cells. Fatty streaks happen, with or without Lp(a). An addendum of "Common Sense."

Given that the guinea pig DOES NOT have Lp(a) but only LDL in a higher ratio to HDL than in wild mice, and that they do incur atherosclerosis upon chronic scurvy, there is no ambiguity that vitamin C deficiency is causal to atherosclerosis WITHOUT invoking apo(a).  Unless a genetically modified variant of guinea pig happens, they will never express apo(a) protein.  The "immunological evidence" proferred by others is obviously a cross-reaction to a different protein, perhaps even apo(a)-like, but certainly it is not lipoprotein(a).  It could not be, rendering any reference to Lp(a) an illogical train of thinking.  However, they do have an ample amount of LDL.  ApoB particles are important to atherogenesis.  We can't just suddenly start ignoring ApoB, not the Lp(a) platform people either.  Without ApoB synthesis, amplified by inflammatory arterial cytokines, there is NO Lp(a).  In mice that can't make vitamin C but also don't have much LDL but a vast majority of HDL, atherosclerosis is limited to a mild physiological hypertrophy, proteoglycan accumulation, and fibrosis, called arteriosclerosis in olden days.  There are some thoracic aortic lesions especially at bifurcations to the digestive system, but little to no atheroma of any visible or clinically significant nature with a majority HDL and few ApoB particles/absolute mass/LDL-cholesterol.  This clearly shows that ApoB containing particles outnumbering ApoA containing particles is a precondition to scurvy induced atherosclerosis, as much as scurvy is a precondition to endothelial dysfunction, the cause and initiation of most atherosclerosis.  This is without getting into the complicated vasa vasorum component which later contributes to erythrocyte evasation into pre-existing plaques where they die and rupture, releasing membrane cholesterol and iron. (It may be in the very near future, the lipid cores and free cholesterol are found to be from intra-plaque hemorrhage from the interdigitating vasa vasorum rather than the vexing (to some people) foam cell plaque "bust.")

That being said, the atherosclerosis that occurs without Lp(a) is much milder than that which occurs with Lp(a).  Atherosclerosis with low Lp(a) and human-esque levels of LDL is much decreased in lesion number, lesion size, and lesion complexity compared to atherosclerosis that occurs with even moderate Lp(a) around.  Lp(a) over 30mg/dL certainly will drive more atherosclerosis, but lower levels of Lp(a) below 20mg/dL also contribute by virtue of its "homing missile" like quality of binding to areas of damage which it finds in the system circulation of 60,000 miles.  It may not matter how much over a certain threshold of Lp(a), but it does potentiate worse and more with ascending blood levels of Lp(a).  There is no question that Lp(a) is atherogenic, but without LDL, how can there be Lp(a)?  It is not an "either-or" or "better or worse" proposition, but where all these facts that the 1000's of highly intelligent global cardiology scientists have seen intersect and what that nexus and conjunction of truth is.

Ox-LDL is a reliable marker of vessel disease and number of vessel involvement

Does this mean that Ox-LDL causes atherosclerosis?  Yes AND No.  It is too low to ever cause atherosclerosis, with circulating levels in multi-vessel CAD being at most 4mg/dL, and normally being 1mg/dL.  However, it is an extremely reliable indicator of CAD, with a level of 3mg/dL Ox-LDL most certainly revealing plaque in the coronaries somewhere.  Its importance is locally in microenvironments where inflammation causes ROS which causes oxidation and acetylation of LDL in the microscopic milieu around the lesion.  If LDL is not oxidized or denatured, it is not "irritating" to the artery, no.  Regular LDL, even in very high concentrations has been proven not to be cytotoxic to the endothelial cell or cause stress fiber contraction.  As I have already said a long time ago, the LDL gets into the artery if and when the endothelial layer (or vasa vasorum) is compromised and has spatially large enough breaches for it to go through.  Vesicular transport would cause LDL to accumulate inside a cell, not outside it, which we'll get to in just a second.

LDL consumption by a cell is highly regulated, and a cell stops internalizing LDL when it has enough, or the cell will turn down its internal synthesis while maintaining internalization.  Extracellular aggregates of native LDL could not be there if they could not reach these subendothelial compartments somehow (increased vascular permeability).  Ox-and Ac-LDL has a special receptor, scavenger receptor, evolutionarily built in humans, the creature with nearly exclusively the majority of fatal heart attacks and strokes, to get rid of apoptotic cells...and denatured LDL.  When scavenger receptor cells encounter ox-LDL, they engulf it without stop.  Call it gobbling, but more accurately, they are the "trash men," the "recycling team," not "police men."  As much as a policeman can clear debris on a highway, and often does for the public benefit, the macrophage can also serve to clean the artery, not "eat it" or "police" it.  The "old concept" people know that fatty streaks, cellular foam cell masses DO NOT burst.  So, the cartoon does call out an inaccuracy - the notion that foam cell lesions form, burst open, and evulse their cholesterol into the artery.  Early on, no.  These are most stable cellular accumulations which would prevent further destabilization of an artery.  Later on, if the condition is unresolved, the damage unmended, and the "artery tumor" becomes hypoxic, like in a tumor, the macrophages would undergo necrosis and form a necrotic core, just like happens in a tumor core.

In human plaques, foam cell formation from the smooth muscle cell component is vastly underestimated because in mice, the majority of foam cells occur from macrophages.  In humans a greater proportion of foam cells happen from the artery cells themselves.  Yet, make no mistake, foam cell "fatty streaks" are found all the time in human atherosclerosis.  They may be there, they may not be, but an astute scientist does not simply ignore foam cells, especially those colocalized upon an Lp(a) deposit.  There are vastly more human plaques that do not have a foam cell component, and these actually are more worrisome because they are less revertible than a foam cell fatty streak.  Why?

The foam cell, like the apo(a) protein, isn't just some random superfluous curiosity, an accident of biology with no purpose.  Foam cells not only contribute to the artery structure temporarily as additional cells with their hydrophobic seal against hemorrhage, cholesterol, but also are participating in transport of excess unused or remaining cholesterol back to the liver, just as LDL delivers useful cholesterol for cell replacement.  Of all cell types, the macrophage is very efficient at this process.  So we see that this too is a useful, purposeful event, that if resolves satisfactorily, signals the macrophages to exit the artery wall, making the fatty streak lump vanish.  Some call it "reverse cholesterol transport," others don't like that name and call it something else.  Once again, you can't just ignore foam cells or dismiss fatty streaks.  Just as Goldstein and Brown didn't just fabricate a mythic fable of LDL homeostasis, despite this encouraging systemic statin poisoning, scientists and pathologists did not 'just make up' a fable of fatty streaks and foam cells being in human arteries.  Truly, these are about repair, rather than a nonsensical auto-attack on the artery wall, although auto-immune arteritis is a real disease too.  It is increasingly important to stay updated with the field to see others' understanding of the issue so that all science and scientists everywhere can eventually come to a real-world consensus.  Or we can rage around ham-fisted and grandstanding, pretending to know everything without the diligence necessary to know everything.

Macrophage reverse cholesterol transport: key to the regression of atherosclerosis?

Collagen IV derived "tumstatin" suppresses tumor growth.

Collagen IV, the basement membrane collagen is probably one of the oldest and most examined subtypes of collagen in oncology.  It is certainly not the only or most important collagen in cancer suppression, or other diseases, but Col4 has been proven to function as a barrier against metastasis in the fibrous capsule in several sophisticated and technically up-to-date studies.

Inhibition of tumor angiogenesis by tumstatin: insights into signaling mechanisms and implications in cancer regression.

"Sudhakar A¹, Boosani CS.

Growing tumors develop additional new blood vessels to meet the demand for adequate nutrients and oxygen, a process called angiogenesis. Cancer is a highly complex disease promoted by excess angiogenesis; interfering with this process poses for an attractive approach for controlling tumor growth. This hypothesis led to the identification of endogenous angiogenesis inhibitors generated from type IV collagen, a major component of vascular basement membrane (VBM). Type IV collagen and the angiogenesis inhibitors derived from it are involved in complex roles, than just the molecular construction of basement membranes. Protease degradation of collagens in VBM occurs in various physiological and pathological conditions and produces several peptides. Some of these peptides are occupied in the regulation of functions conflicting from those of their original integral molecules. Tumstatin (alpha3(IV)NC1), a proteolytic C-terminal non-collagenous (NC1) domain from type IV collagen alpha3 chain has been highlighted recently because of its potential role in anti-angiogenesis, however its biological actions are not limited to these processes. alpha3(IV)NC1 inhibits proliferation by promoting endothelial cell apoptosis and suppresses diverse tumor angiogenesis, thus making it a potential candidate for future cancer therapy. The present review surveys the physiological functions of type IV collagen and discovery of alpha3(IV)NC1 as an antiangiogenic protein with a comprehensive overview of the knowledge gained by us towards understanding its signaling mechanisms."

Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth. 

"

Hamano Y¹, Kalluri R.

Angiogenesis, the formation of new blood vessels, is required for physiological development of vertebrates and repair of damaged tissue, but in the pathological setting contributes to progression of cancer. During tumor growth, angiogenesis is supported by up-regulation of angiogenic stimulators (pro-angiogenic) and down-regulation of angiogenic inhibitors (anti-angiogenic). The switch to the angiogenic phenotype (angiogenic switch) allows the tumors to grow and facilitate metastasis. The bioactive NC1 domain of type IV collagen alpha3 chain, called tumstatin, imparts anti-tumor activity by inducing apoptosis of proliferating endothelial cells. Tumstatin binds to alphaVbeta3 integrin via a mechanism independent of the RGD-sequence recognition and inhibits cap-dependent protein synthesis in the proliferating endothelial cells. The physiological level of tumstatin is controlled by matrix metalloproteinase-9, which most effectively cleaves it from the basement membrane and its physiological concentration in the circulation keeps pathological angiogenesis and tumor growth in check. These findings suggest that tumstatin functions as an endogenous inhibitor of pathological angiogenesis and functions as a novel suppressor of proliferating endothelial cells and growth of tumors."

Collagen XIX is strongly anti-tumorigenic

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth.

Mol Cancer Ther. 2007 Feb;6(2):506-14.

The NC1 domain of type XIX collagen inhibits in vivo melanoma growth.

Ramont L¹, Brassart-Pasco S, Thevenard J, Deshorgue A, Venteo L, Laronze JY, Pluot M, Monboisse JC, Maquart FX.

Type XIX collagen is a minor collagen that localizes to basement membrane zones, together with types IV, XV, and XVIII collagens. Because several NC1 COOH-terminal domains of other chains from basement membrane collagens were reported to exhibit antitumor activity, we decided to study the effects of the NC1(XIX) collagen domain on tumor progression using an experimental in vivo model of mouse melanoma. We observed a 70% reduction in tumor volume in NC1(XIX)-treated mice compared with the corresponding controls. Histologic examination of the tumors showed a strong decrease in tumor vascularization in treated mice. In vitro, NC1(XIX) inhibited the migrating capacity of tumor cells and their capacity to invade Matrigel. It also inhibited the capacity of human microvascular endothelial cells to form pseudotubes in Matrigel. This effect was accompanied by a strong inhibition of membrane type-1 matrix metalloproteinase (matrix metalloproteinase-14) and vascular endothelial growth factor expression. Collectively, our data indicate that the NC1 domain of type XIX collagen exerts antitumor activity. This effect is mediated by a strong inhibition of the invasive capacities of tumor cells and antiangiogenic effects. NC1(XIX) should now be considered as a new member of the basement membrane collagen-derived matrikine family with antitumor and antiangiogenic activity.

PMID: 17308049

 

The NC1 domain of type XIX collagen inhibits melanoma cell migration. 

Eur J Dermatol. 2010 Nov-Dec;20(6):712-8. doi: 10.1684/ejd.2010.1070. Epub 2010 Sep 14.
 The NC1 domain of type XIX collagen inhibits melanoma cell migration.

Toubal A¹, Ramont L, Terryn C, Brassart-Pasco S, Patigny D, Sapi J, Monboisse JC, Maquart FX.

Type XIX collagen is a minor collagen that localizes to basement membrane zones. We previously demonstrated that the C-terminal NC1 domain of type XIX collagen inhibits tumor growth in vivo. In the present study, we analyzed the effects of the NC1(XIX) collagen domain on migratory behaviour of melanoma B16F10 cells. We found that NC1(XIX) do not inhibit melanoma cell proliferation. On the contrary, NC1(XIX) strongly inhibited the migratory capacities of melanoma cells in the scratch wound model and in Ibidi® devices: cell migration speed was 7.69 ± 1.49 μm/h for the controls vs 6.64 ± 0.82 μm/h for cells incubated with 30 μmol/L NC1(XIX) and 5.72 ± 0.67 μmol/h with 60 μmol/L NC1(XIX). Similar results were obtained with UACC 903 human melanoma cells. Further work will be necessary to elucidate the molecular mechanisms of this migration inhibition. It may, however, explain, at least partially, the inhibition of tumor growth that we observed in vivo.

PMID: 20840910

 

 

Loss of Collagen XV Causes Muscle Tissue and Capillary Degeneration

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice.

From:

Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1194-9. Epub 2001 Jan 23.

Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice.

Eklund L¹, Piuhola J, Komulainen J, Sormunen R, Ongvarrasopone C, Fássler R, Muona A, Ilves M, Ruskoaho H, Takala TE, Pihlajaniemi T.

Muscle histology: focal areas of degeneration, regeneration, and variation in fiber size. Hematoxylin and eosin-stained sections of the gastrocnemius (A), triceps brachii (B), paraspinal (C), and quadriceps (D) muscles of 6-month-old null mice showing cell degeneration (curved arrows, A and C) with macrophage infiltration (A), regenerative fibers (thin arrow, B), central nuclei (thin arrow, C), and increased variation in fiber size with atrophic muscle fibers (D, arrowheads) compared with age-matched wild-type mice (E). Original magnifications: A and D, ×300; B, ×200; C and E, ×80.

Ultrastructural changes in capillaries. Electron microscopy of heart capillaries from a wild-type (A) and a null mouse (B) with swollen endothelial cells (asterisks). The lumen is indicated by a white arrow. Skeletal muscle capillaries from a wild-type (C) and a mutant mouse (D) showing luminal narrowing and folding of endothelial cells.

Effect of isoproterenol stimulation on developed pressure in (A) 6-month-old and (B) 12-month-old mutant and wild-type mice. The responses to β-agonists were measured in terms of the ratio of the maximal value of the developed pressure (DP) to the basal level before the isoproterenol perfusion in Col15a1^−/− (●: A, n = 7; B, n = 11) and Col15a1^+/+ (□: A, n = 7; B, n = 8) mice. The symbols represent mean ± SEM. Significant differences between the Col15a1^−/− and Col15a1^+/+ mice are indicated by asterisks as follows: *, P < 0.05, **, P < 0.01. The basal pressure was 31.7 ± 5.0 and 27.3 ± 5.0 mmHg for the 6-month-old control and null mice, respectively, and 20.2 ± 3.4 and 20.8 ± 2.0 mmHg for the 1-year-old mice (mean ± SEM).