another side to the heart toxicity debate

[Guest guest]

Just to add another angle to this debate. Here's an abstact showing

that due to Gleevec's ability to inhibit PDGF, it may actually

protect the heart in some ways. I wonder if this could also explain

why many of us have low blood pressure?

Tracey

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1: Hypertension. 2006 Jan 23; [Epub ahead of

print] Links

Imatinib Attenuates End-Organ Damage in

Hypertensive Homozygous

TGR(mRen2)27 Rats.

Schellings MW, Baumann M, van Leeuwen RE,

Duisters RF, Janssen SH, Schroen

B, Peutz-Kootstra CJ, Heymans S, Pinto YM.

Experimental and Molecular Cardiology,

Cardiovascular Research Institute

Maastricht, Maastricht University, the

Netherlands; Department of

Pharmacology, Maastricht University, the

Netherlands; and Department of

Pathology, University Hospital Maastricht, the

Netherlands.

Imatinib specifically inhibits receptor tyrosine

kinase signaling and is

clinically used to treat leukemia. Receptor

tyrosine kinases not only

mediate tumor growth but also initiate adverse

signaling in heart failure.

We investigated whether imatinib, by inhibiting

the platelet-derived growth

factor receptor-beta (PDGFRbeta), prevents

cardiac and renal damage in

TGR(mRen2)27 (Ren2) rats. Eight-week-old male

homozygous Ren2 and Sprague

Dawley rats were treated either with imatinib (30

mg/kg; STI-571) or

placebo for 8 weeks (Ren2 n=12 for each group;

Sprague Dawley n=6 for each

group). Imatinib did not affect blood pressure or

left ventricular (LV)

hypertrophy in both groups. Imatinib attenuated

the decline in fractional

shortening (imatinib versus Ren2 placebo

45+/-4.5% versus 32+/-3%; n=7-11;

P<0.05) and in diastolic function in Ren2 rats

(baseline diastolic dP/dt

corrected for systolic blood pressure Ren2

imatinib versus Ren2 placebo

38.6+/-0.67 versus 35.3+/-0.41 [1 . s(-1)];

n=7-11; P<0.05). This was

associated with decreased cardiac fibrosis and

decreased activation of

PDGFRbeta and extracellular signal-regulated

kinase 1/2. Renal

microvascular hypertrophy and perivascular

fibrosis in Ren2 rats were

significantly decreased by imatinib. In vitro,

imatinib blocked angiotensin

II-induced activation of the PDGFRbeta and

significantly decreased

fibroblast proliferation and collagen production.

In conclusion, imatinib

did not affect LV hypertrophy but attenuated the

decline in cardiac

function and reduced renal microvascular damage

associated with reduced

activation of the PDGFRbeta. The simultaneous

improvement in both heart and

kidneys suggests that inhibition of the PDGFRbeta

has broad protective

effects that may provide novel avenues for a

blood pressure-independent

protection against end-organ damage.