*2.2. Rat Models of Cardiac Hypertrophy and KLF15*

KLF15 expression was examined in 2 models of hypertension—the transgenic TGR(mRen2)27 rat (Ren-2) [15] and the high salt fed Dahl salt-sensitive rat [19]. The Ren-2 rat is characterized by severe hypertension, LVH, suppression of the kidney renin-angiotensin system and unchanged or suppressed levels of plasma renin, Ang I and II and angiotensinogen compared to wildtype rats [20]. Cardiac KLF15 expression was reduced at an early stage of LVH. In an elegant series of experiments, cardiac biopsies were taken from the rats with a similar degree of cardiac hypertrophy and normal systolic function, and followed over time. KLF15 mRNA expression decreased more in the hypertrophied hearts that progressed to heart failure compared to control and compensated rats, suggesting that expression of KLF15 may play a role in the prevention of heart failure.

Dahl salt-sensitive rats fed a high salt diet developed hypertension-induced LVH at 11 weeks, with LV dilatation and heart failure at 17 weeks [19]. Cardiac KLF15 mRNA was significantly reduced with LVH and decreased further with the development of heart failure. This change was associated with increased ANP gene expression with LVH and a further increase in levels with the development of heart failure [19].

Aortic stenosis is a common cause of LVH and KLF15 expression has been examined in two experimental models of aortic constriction—transaortic constriction and aortic banding. In adult Sprague-Dawley rats, KLF15 mRNA expression was non-significantly reduced at 2 days post transaortic constriction with a significant reduction by 7 days post transaortic constriction [13].

Yu et al. [17] conducted studies in rats with pressure overload secondary to aortic banding and examined the effect of debanding and unloading pressure at 3 and 6-weeks. Aortic banding increased ejection fraction and LV pressure compared to the sham group, and both improved after debanding. At both 3 and 6-weeks after aortic banding, rats had decreased KLF15 mRNA, and increased CTGF, transforming growth factor-β (TGFβ) and myocardin-related transcription factor A (MRTF-A) with fibrosis and increased collagen I and III mRNA compared to sham-operated rats. KLF15 levels dropped further in the 6-week banded animals. Aortic debanding resulted in a decrease in collagen mRNA, increased KLF15 and reduced TGFβ mRNA.
