Abstract 15674: Notch3/rbpjk Signaling Pathway in the Coronary Arteries is Involved in the Development of Heart Failure in Response to Hypertension
Background: Notch3, a receptor expressed in vascular smooth muscle cells (VSMC), plays a key role in the integrity of resistance arteries by controlling the maturation of VSMC through RBPJk, a canonical Notch transcriptional factor. We hypothesized that Notch3 signaling pathway in the VSMCs of the coronary arteries might play a key role in the cardiac adaptation to pressure-overload.
Methods: To eliminate congenital defect biases, we used mice in which conditional tamoxifen- selective deletion of RBPJk in VSMC was induced at the age of 4 weeks (SMMHC-CRE ER T2, RBP-JK loxp/loxp). Seven weeks later, hypertension was induced in control (C) mice (n= 10) and those with RBPJk deletion (SM-RBPJ-KO, n = 13) by infusion of Angiotensin 2 (Ang2) (1μg/kg/min) using Alzet minipumps after surgery.
Results: In response to Ang2, SM-RBPJ-KO and control mice showed similar hypertension (159 ±7 mmHg vs 150±10 mmHg). By day 8 after surgery, SM-RBPJ-KO mice only developed a severe heart failure with anarsaca. These mice showed a decrease in shortening fraction (-42%, p<0.01), a left ventricular dilatation (+15%, p<0.01), and a ventricular hypertrophy (+12%, p<0.05) when compared to C + Ang2. As expected, C + Ang 2 hearts showed an increase in ANP, B-MHC and Gal-3 (+76%, +55%, +46%, p<0.05 respectively vs C) mRNA expressions, whereas SM-RBPJ-KO hearts exhibited even higher induction of ANP (+48%, p<0.01), Gal-3 (+74%, p<0.01), CD68 (+55%, p<0.05) and collagen-3 (+78%, p<0.01) when compared to C + Ang2. This cardiac phenotype confirmed the severe heart failure. Interestingly, immuno-morphometric analysis showed an arteriolar rarefaction in SM-RBPJ-KO + Ang2 mice associated with a lack of angiogenic signaling pathway revealed by a decrease in VEGFa and angiopoietin 2 mRNAs (-50%, and -52%, p<0.05, respectively vs. C + Ang2).
Conclusion: We provide evidence that in adulthood, dysfunction of the Notch3/RBPJk signaling pathway in the coronary arteries contributes in the aggravation of heart failure in response to rapid increase in blood pressure.
Author Disclosures: A. Monfort: None. H. Ragot: None. E. Polidano: None. R. Merval: None. C. Delcayre: None. C. Chatziantoniou: None. J. Samuel: None. A. Cohen-Solal: None.
- © 2014 by American Heart Association, Inc.