74 Importantly, Hedgehog Pathway miR-1 was downregulated prior to hypertrophy development (1d) and persisted until later stages of hypertrophy (14d), and specifically up to 1 week before the presentations of HF in the TAC model. Moreover, five of the miRNAs that were upregulated during

hypertrophy development (7d) (miR-199a, -199a*, -199b, -21, -214) and persisted until day 14 were the ones that exhibited the greatest change (>2 fold). 74 These findings indicate a distinct stage-specific role of miR-1 and the latter five miRNAs in the development of hypertrophy in the TAC mouse model. Similar miRNA expression changes were observed in another study, utilizing both the TAC mouse model and mice with cardiac-specific expression of activated calcineurin (CnA) (aimed at inducing pathological cardiac remodeling and hypertrophic growth). Accordingly, 42 miRNAs were differentially expressed in TAC hearts and 47 in CnA, with the two groups sharing 21 upregulated and 7 dowregulated miRNAs. Importantly, six of these miRNAs (miR-23,

-24, -125, -195, -199a, -214) were consistent with findings in idiopathic end-stage human failing heart tissue, suggesting the conservation of pathogenic processes across species and highlighting their importance in HF. 70 The comparative study of a preload versus afterload cardiac hypertrophy mouse model, revealed that miRNA expression changes several days post TAC or shunt, suggesting that these mechanisms are involved in the later stages of remodeling post cardiac overload. The hypertrophy related miRNA- 133, -30 and -208, were regulated only in the afterload model, consistently with the direct role

of miR-208 in ß-MHC upregulation. 73,74,92 The preload hypertrophy model presented with changes in miR-140, -320 and -455. MiR-320 has been associated with apoptosis, while both miR-320 and miR-140 are upregulated in human HF. 79 Studies conducted in the left ventricles of a rat model of hypertrophy induced by banding of the ascending aorta, detected four upregulated miRNAs (miR-23a, -27b, -125b and -195), 14 days post operation, when the hypertrophy was already established (left ventricle weight/ body weight ratio increased by 65%). 93 Importantly, miR-23a,-27b and -195 are known to favor CMC hypertrophic Batimastat growth (see section 3.c.i). The observed changes in the expression of miRNAs in this rat model of hypertrophy are in line with previous studies in mice and human tissue, thus strengthening the notion of intra-species conservation of HF-related miRNA mechanisms. miRNA signatures change during disease progression to HF The expression of miRNA is a highly dynamic process, with different molecules and combinations thereof being implicated in the different stages of conditions leading to HF. The most representative example of miRNA expression pattern shift during HF development is that of miR-1 and miR-133.