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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\u2010specific ZKSCAN3 knockout (Z3K) disrupts autophagy activation and repression balance and exacerbates cardiac pressure\u2010overload\u2010induced remodeling following transverse aortic constriction (TAC). Indeed, Z3K mice had an enhanced mortality compared to control (Con) mice following TAC. Z3K\u2010TAC mice that survived exhibited a lower body weight compared to Z3K\u2010Sham. Although both Con and Z3K mice exhibited cardiac hypertrophy after TAC, Z3K mice exhibited TAC\u2010induced increase of left ventricular posterior wall thickness at end diastole (LVPWd). Conversely, Con\u2010TAC mice exhibited decreases in PWT%, fractional shortening (FS%), and ejection fraction (EF%). Autophagy genes (<jats:italic>Tfeb, Lc3b,<\/jats:italic> and <jats:italic>Ctsd<\/jats:italic>) were decreased by the loss of ZKSCAN3. TAC suppressed <jats:italic>Zkscan3, Tfeb, Lc3b<\/jats:italic>, and <jats:italic>Ctsd<\/jats:italic> in Con mice, but not in Z3K. The <jats:italic>Myh6\/Myh7<\/jats:italic> ratio, which is related to cardiac remodeling, was decreased by the loss of ZKSCAN3. Although <jats:italic>Ppargc1a<\/jats:italic> mRNA and citrate synthase activities were decreased by TAC in both genotypes, mitochondrial electron transport chain activity did not change. Bi\u2010variant analyses show that while in Con\u2010Sham, the levels of autophagy and cardiac remodeling mRNAs form a strong correlation network, such was disrupted in Con\u2010TAC, Z3K\u2010Sham, and Z3K\u2010TAC. <jats:italic>Ppargc1a<\/jats:italic> also forms different links in Con\u2010sham, Con\u2010TAC, Z3K\u2010Sham, and Z3K\u2010TAC. We conclude that ZKSCAN3 in cardiomyocytes reprograms autophagy and cardiac remodeling gene transcription, and their relationships with mitochondrial activities in response to TAC\u2010induced pressure overload.<\/jats:p>","DOI":"10.14814\/phy2.15686","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T10:16:53Z","timestamp":1683281813000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cardiomyocyte <scp>ZKSCAN3<\/scp> regulates remodeling following pressure\u2010overload"],"prefix":"10.14814","volume":"11","author":[{"given":"Xiaosen","family":"Ouyang","sequence":"first","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayan","family":"Bakshi","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama at Birmingham  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