Microarray Analysis Provides a Link between Adenylyl Cyclase Type 5 and Pressure Overload Hypertrophy

Abstract

Adenylyl cyclase type 5 and 6 (AC5 and AC6) are the major cardiac isoforms, but may affect cardiac pathophysiology differently. To investigate genes regulated by AC5 and AC6 regarding hypertrophy, we performed microarray‐based gene expression analysis of transgenic mice (TG) with cardiac specific overexpression of AC5 or AC6, and compared them with wild type with transverse aortic constriction (WT‐TAC). We detected a positive correlation of global gene expression profiles between AC5 TG and WT‐TAC, but not between AC6 TG and WT‐TAC. Baseline measures of AC5 high‐overexpression resulted in increased LV/BW (3.5±0.2) compared with WT (3.1±0.1) and AC6 TG (3.2±0.0). We found that commonly up‐regulated genes in both AC5 TG and WT‐TAC, but down‐regulated in AC6 TG were significantly, p<0.001, associated with extracellular matrix (ECM) organization and biogenesis. In addition hypertrophy related genes were up‐regulated in both AC5 TG and WT‐TAC, but not in AC6 TG. We confirmed those results by quantitative real‐time PCR. In summary, AC5 TG mice, even at baseline, have a similar gene expression profile to WT mice with TAC, which could explain the predisposition of AC5 TG to pressure overload hypertrophy. The microarray data also suggest that ECM related genes, which are regulated differently in AC5 and AC6 may be responsible for the adverse response of LV remodeling after pressure overload in AC5.