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| Status |
Public on Sep 14, 2010 |
| Title |
Regression of Cardiac Hypertrophy and Attenuation of Progression to Heart Failure by Paricalcitol Therapy in Rats |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
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| Summary |
Background: Vitamin D deficiency is associated with cardiac hypertrophy and heart failure, and vitamin D therapy prevents the progression of cardiac hypertrophy in animal models. Here, we examine whether vitamin D therapy regresses pre-existing cardiac hypertrophy, and prevents the progression to heart failure.
Methods and Results: When male Dahl salt-sensitive (DSS) rats are fed a high salt (HS) diet, all rats develop cardiac hypertrophy after 5 weeks (H). Thereafter, rats were treated with vehicle (V), paricalcitol (PC, an active vitamin D analog at 200ng, IP 3x/wk), enalapril (EP, 90ug/day), and PC+EP. All groups were continued on the HS diet and evaluated after 4 weeks of therapy. The PC and PC+EP, but not the V and EP-only groups, showed significant regression of pre-existing cardiac hypertrophy. The signs of decompensated heart failure were evident in the vehicle-treated group; these heart failure parameters significantly improved with PC, EP or PC+EP therapy. The expression of PKCe, which is regulated by Ca2+ and known to stimulate cardiac hypertrophy, was significantly increased in the vehicle group, and PC, EP or PC+EP effectively decreased PKCe activation. We also observed normalization of genetic alterations during progression to heart failure with PC treatment.
Conclusions: PC treatment resulted in both the regression of pre-existing cardiac hypertrophy, and the attenuation of the progression to heart failure, compared to improvement in progression to heart failure by EP alone. These beneficial findings in the heart were associated with inhibition of PKCe activation, and reversal of gene alterations.
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| Overall design |
Male Dahl salt-sensitive rats (Harlan Sprague–Dawley, Somerville, NJ) were bred and fed a normal diet until 6 weeks of age. To generate pressure overload cardiac hypertrophy, they were then fed a high salt (6%NaCl) diet for the next 5 weeks. Data for baseline hypertrophic group (H) was obtained at the end of 11 weeks. Among H group animals, they were divided as follows and treated for an additional 4 weeks: 1) continuation of the HS diet with vehicle injection (H+V); 2) continuation of the HS diet with paricalcitol (19-nor-1,25-(OH)2 D2) (PC) (200ng IP 3x/wk) injection (H+PC); 3) continuation of the HS diet with low dose enalapril (EP), an angiotensin-converting enzyme inhibitor, infusion via osmotic pump and vehicle injection (H+EP+V); and 4) continuation of the HS diet with low dose EP infusion via osmotic pump and PC (200ng IP 3x/wk) injection (H+EP+PC). PC was prepared with 95% propylene glycol and 5% ethyl alcohol solution and administered three times a week on Monday, Wednesday, and Friday for 4 consecutive weeks. Vehicle groups received vehicle injections on the same schedule. Two groups of rats were implanted with pumps to deliver EP for 4 weeks. Since the reduction in blood pressure (BP) from high doses of EP would have effects on cardiac hypertrophy and progression to heart failure, we used low dose EP at 90ug/day, a maximum dose that did not significantly decrease BP in these rats, to study the effects of EP and PC that are independent of BP.
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| Contributor(s) |
Bae S, Yalamarti B, Ke Q, Choudhury S, Karumanchi SA, Kroeger PE, Thadhani R, Kang PM |
| Citation(s) |
21565836 |
| Submission date |
Sep 13, 2010 |
| Last update date |
Jul 31, 2017 |
| Contact name |
Paul Kroeger |
| E-mail(s) |
paul.e.kroeger@abbott.com
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| Organization name |
Abbott Laboratories
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| Department |
R4DI, AP52-1N
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| Street address |
200 Abbott Park Road
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| City |
Abbott Park |
| ZIP/Postal code |
60048 |
| Country |
USA |
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| Platforms (1) |
| GPL1355 |
[Rat230_2] Affymetrix Rat Genome 230 2.0 Array |
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| Samples (19)
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| GSM593349 |
Heart_high salt_control_rep4 |
| GSM593350 |
Heart_high salt+vehicle_rep1 |
| GSM593351 |
Heart_high salt+vehicle_rep2 |
| GSM593352 |
Heart_high salt+vehicle_rep3 |
| GSM593353 |
Heart_high salt+vehicle_rep4 |
| GSM593354 |
Heart_high salt_paricalcitol_rep1 |
| GSM593355 |
Heart_high salt_paricalcitol_rep2 |
| GSM593356 |
Heart_high salt_paricalcitol_rep3 |
| GSM593357 |
Heart_high salt_paricalcitol_rep4 |
| GSM593358 |
Heart_high salt_enalapril+vehicle_rep1 |
| GSM593359 |
Heart_high salt_enalapril+vehicle_rep2 |
| GSM593360 |
Heart_high salt_enalapril+vehicle_rep3 |
| GSM593361 |
Heart_high salt_enalapril+paricalcitol_rep1 |
| GSM593362 |
Heart_high salt_enalapril+paricalcitol_rep2 |
| GSM593363 |
Heart_high salt_enalapril+paricalcitol_rep3 |
| GSM593364 |
Heart_high salt_enalapril+paricalcitol_rep4 |
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| Relations |
| BioProject |
PRJNA130203 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE24110_RAW.tar |
51.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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