Molecular Phenotyping of the Natriuretic Peptide and Renin-Angiotensin Systems in the Post-Myocardial Infarction Left Ventricle and Scar

Background: Myocardial infarction (MI) is a major consequence of ischemic heart disease and progression from MI to heart failure (HF) continues to increase. Indeed, the formation and extent of LV scarring due to MI contributes to HF progression and represents a target of therapeutic intervention, as the scar contains living fibroblast like cells. Further, studies continue to support the role of the renin-angiotensin system (RAS) contributing to adverse post-MI fibrotic remodeling, which are opposed by the cardioprotective actions of the natriuretic peptide system (NPS). While the cellular responses of the RAS and NPS have been studied in the viable post-MI myocardium, it is unknown whether the RAS and NPS are expressed, and altered, in the LV scar that is increasingly recognized as a biologically active tissue. Hypothesis: This study tested the hypothesis that NPS receptors and their endogenous ligands and components of the RAS are present and altered in the post-MI scar. Methods: MI was induced by left coronary artery ligation in wistar rats and sham-operated (S) rats served as controls (n = 10/group). LV structure and function was assessed at 4 weeks post-MI and included hypertrophy, EF and interstitial fibrosis (remote region) by picrosirius red staining. Microarray analysis (Affymetrix Rat Genome GeneChip and GeneSifter software) was performed on 3 sets of LV tissue: 1) scar; 2) remote region distal to the scar and 3) sham-operated LV. Transcriptional identification and changes in the NPS [natriuretic peptide (NP) ligands: ANP, BNP, CNP; natriuretic peptide receptors (NPR): NPR-A, NPR-B and NPR-C] and RAS components [renin, angiotensinogen, angiotensin converting enzyme (ACE), angiotensin II receptor (ATR)1 and ATR2] were assessed in LV tissues. Data are presented as Mean ± SE. *P < .05 between groups. Results: MI was characterized by a significant increase in LV hypertrophy (S: 2.06 ± 0.03, MI: 2.57 ± 0.07 mg/g*) as well as LV fibrosis (S: 2.4 ± 0.1, MI:4.5 ± 0.6%*) and a significant decrease in EF (S:79 ± 1, MI:49 ± 4%*). Microarray analysis indicated the expression of all genes related to the NPS and RAS in LV scar and the remote region tissue. Notably, ANP was significantly up-regulated in both the LV scar and remote region compared to sham LV, while the ATR1, ACE and NPR-B genes were significantly up-regulated in the scar compared to other LV tissues. Conclusion: We report that the NPS (anti-hypertrophic, anti-fibrotic, and anti-apoptotic) and RAS (pro- hypertrophic, pro-fibrotic and pro-apoptotic) are molecularly activated within the scar, in addition to the viable myocardium. Moreover, this activation may contribute to the structural and functional integrity as well as remodeling of the heart following MI. These findings suggest key differential molecular modulation of the NPS and RAS in the regulation post-MI fibrotic remodeling, which may provide strategic insights into the development of novel scar-modifying therapies to prevent the progression to HF.