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• W4210536620 abstract "Klotho is an aging-suppressor gene. Klotho gene deficiency causes heart failure in Klotho-hypomorphic mutant (KL (-/-)) mice. RNA-seq and western blot analysis showed that adenylyl cyclase type IV (AC4) mRNA and protein expression was largely decreased in cardiomyocytes of KL (-/-) mice. The objective of this study was to investigate whether in vivo cardiac-specific expression of AC4 gene protects against Klotho deficiency-induced heart failure. Interestingly, in vivo AAV-based cardiac-specific AC4 gene expression increased left ventricular fractional shortening, ejection fraction, stroke volume, and left ventricular end-diastolic volume in KL (-/-) mice, suggesting that cardiac-specific AC4 gene expression improves Klotho deficiency-induced heart dysfunction. Cardiac-specific AC4 gene expression also decreased Klotho deficiency-induced cardiac hypertrophy. Cardiac-specific AC4 gene expression alleviated Klotho deficiency-induced cardiac fibrosis and calcification. Furthermore, cardiac-specific AC4 gene expression attenuated mitochondrial dysfunction, superoxide accumulation and cardiomyocyte apoptotic cell death. Thus, downregulation of AC4 may contribute to Klotho deficiency-induced heart failure. Mechanistically, AAV2/9-αMHC-AC4 increased cardiomyocytic cAMP levels and thus regulated the PKA-PLN-SERCA2 signal pathway, which is critical in modulating calcium flux and mitochondrial function. In conclusion, cardiac-specific AC4 gene expression protects against Klotho deficiency-induced heart failure through increasing cardiomyocytic cAMP levels, which alleviates cAMP-dependent mitochondrial dysfunction, superoxide accumulation and apoptotic cell death. AC4 regulates superoxide levels via the cAMP-PKA pathway. AC4 could be a potential therapeutic target for heart failure associated with Klotho deficiency. Heart failure is the major cause of mortality in patients with chronic kidney disease (CKD). A decrease in Klotho levels is linked to CKD." @default.
• W4210536620 created "2022-02-08" @default.
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• W4210536620 date "2022-06-01" @default.
• W4210536620 modified "2023-10-14" @default.
• W4210536620 title "In Vivo Cardiac-specific Expression of Adenylyl Cyclase 4 Gene Protects against Klotho Deficiency-induced Heart Failure" @default.
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• W4210536620 doi "https://doi.org/10.1016/j.trsl.2022.01.006" @default.
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