Cardiomyocyte ZKSCAN3 regulates remodeling following pressure‐overload

Autophagy is important for protein and organelle quality control. Growing evidence demonstrates that autophagy is tightly controlled by transcriptional mechanisms, including repression by zinc finger containing KRAB and SCAN domains 3 (ZKSCAN3). We hypothesize that cardiomyocyte‐specific ZKSCAN3 knockout (Z3K) disrupts autophagy activation and repression balance and exacerbates cardiac pressure‐overload‐induced remodeling following transverse aortic constriction (TAC). Indeed, Z3K mice had an enhanced mortality compared to control (Con) mice following TAC. Z3K‐TAC mice that survived exhibited a lower body weight compared to Z3K‐Sham. Although both Con and Z3K mice exhibited cardiac hypertrophy after TAC, Z3K mice exhibited TAC‐induced increase of left ventricular posterior wall thickness at end diastole (LVPWd). Conversely, Con‐TAC mice exhibited decreases in PWT%, fractional shortening (FS%), and ejection fraction (EF%). Autophagy genes (Tfeb, Lc3b, and Ctsd) were decreased by the loss of ZKSCAN3. TAC suppressed Zkscan3, Tfeb, Lc3b, and Ctsd in Con mice, but not in Z3K. The Myh6/Myh7 ratio, which is related to cardiac remodeling, was decreased by the loss of ZKSCAN3. Although Ppargc1a mRNA and citrate synthase activities were decreased by TAC in both genotypes, mitochondrial electron transport chain activity did not change. Bi‐variant analyses show that while in Con‐Sham, the levels of autophagy and cardiac remodeling mRNAs form a strong correlation network, such was disrupted in Con‐TAC, Z3K‐Sham, and Z3K‐TAC. Ppargc1a also forms different links in Con‐sham, Con‐TAC, Z3K‐Sham, and Z3K‐TAC. We conclude that ZKSCAN3 in cardiomyocytes reprograms autophagy and cardiac remodeling gene transcription, and their relationships with mitochondrial activities in response to TAC‐induced pressure overload. Our study demonstrated that ZKSCAN3 level is significantly decreased, along with TFEB, in response to pressure overload. We then generated cardiomyocyte‐specific ZKSCAN3 knockout (Z3K) mice, and found that Z3K mice had an enhanced mortality compared to control (Con) mice following TAC, and those that survived exhibited a lower body weight. Significant changes of transcription landscapes were found in Z3K mice after sham surgery.