Currently, there is a largely unmet need for therapeutic strategies to combat diastolic heart failure. The prevention and reversal of left ventricular (LV) fibrosis, a known contributor to diastolic dysfunction, may provide a solution for this clinical problem. Relaxin, via activation of its primary receptor RXFP-1, blocks collagen synthesis and enhances collagen degradation and thus, is a potent antifibrotic agent. The work presented here tested the hypotheses that the natural relaxin receptor-ligand system is upregulated in the fibrotic LV with diastolic dysfunction and exogenous relaxin administration can reverse LV fibrosis and restore diastolic function.
Several rat models of age- and hypertension-associated LV fibrosis were studied: young versus aged spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY) versus SHR, and control Sprague-Dawley (SD) rats versus renin overproducing transgenic (MREN) rats. An upregulation of the endogenous relaxin receptor-ligand system determined by quantitative real-time PCR was present in each of the fibrotic animal models, specifically a ∼2- 4.5 fold increase in mRNA expression of RXFP-1 and a tendency towards increased relaxin expression (∼1.5 fold).
In the MREN rat model, this endogenous upregulation of the relaxin receptor-ligand system occurred in parallel with significantly elevated LV mRNA expression of known fibrotic biomarkers (TGFβ, BNP, and MMP2), suggesting an adaptive response. MREN rats also exhibited significant LV hypertrophy, fibrosis, and diastolic dysfunction (increased LV and myocardial passive stiffness and slowed relaxation), while systolic function was unaltered. Administration of recombinant human relaxin (rhRLX, 0.5 mg/kg/day for 14 days) to MREN rats did not affect hypertension or hypertrophy. However, rhRLX administration significantly reversed mRNAs of fibrotic biomarkers and RXFP-1 and LV fibrosis in MREN rats. These changes were associated with significantly reduced passive stiffness and this beneficial effect was consistent even under the condition of stress (increased heart rate). In contrast, rhRLX administration did not alter LV relaxation.
We conclude that the endogenous LV relaxin receptor-ligand system exerts an adaptive response in a fibrotic environment. The ability of exogenous relaxin administration to reverse LV fibrosis and improve diastolic function may provide a novel strategy for treating diastolic heart failure.
|Advisor:||Shroff, Sanjeev G.|
|School:||University of Pittsburgh|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 76/08(E), Dissertation Abstracts International|
|Keywords:||Diastolic dysfunction, Diastolic heart failure, Left ventricular fibrosis, Relaxin, Relaxin receptor, TGR (mREN2)27|
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