The spontaneously hypertensive rat (SHR), one of the most widely used model of essential hypertension, is predisposed to left ventricular hypertrophy, myocardial fibrosis and metabolic disturbances. Recently, quantitative trait loci influencing blood pressure, left ventricular mass and heart interstitial fibrosis were mapped in the vicinity of Plzf (promyelocytic leukemia zinc finger) candidate gene. To identify Plzf as a quantitative trait gene, we targeted Plzf in the SHR using the TALEN technique and obtained SHR line harboring nonfunctional Plzf gene. SHR rats with down-regulated Plzf gene versus SHR wild type controls exhibited reduced adiposity, lower serum and liver triglycerides and cholesterol and better glucose tolerance. In addition, SHR rats with targeted Plzf gene showed significant amelioration of cardiomyocyte hypertrophy and cardiac fibrosis. Gene expression profiles in the liver and expression of selected genes in the heart revealed differentially expressed genes that play role in metabolic pathways, PPAR signaling and cell cycle regulation. These results provide evidence for an important role of Plzf in regulation of metabolic and cardiac traits in the rat and suggest a crosstalk between cell cycle regulators, metabolism, cardiac hypertrophy and fibrosis.

Interstitial fibrosis and cardiomyocyte size reduction in spontaneously hypertensive rat (SHR)-Plzf^+/-  and SHR control rats. A. Interstitial fibrosis is clearly discernible in a section stained with Sirius Red in SHR, much less pronounced in  SHR-Plzf^+/-  rats. B. Cardiomyocyte size was significantly reduced in SHR-Plzf^+/-  rats when compared with SHR controls.

*P<0.01.

Liška F, Landa V, Zídek V, Mlejnek P, Šilhavý J, Šimáková M, Strnad H, Trnovská J, Škop V, Kazdová L, Starker CG, Voytas DF, Izsvák Z, Mancini M, Šeda O, Křen V, Pravenec M. Downregulation of Plzf Gene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat. Hypertension. 2017 Jun;69(6):1084-1091