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GJA1-20k attenuates Ang II-induced pathological cardiac hypertrophy by regulating gap junction formation and mitochondrial function


Cardiac hypertrophy (CH) is characterized by an increase in cardiomyocyte size, and is the most common cause of cardiac-related sudden death. A decrease in gap junction (GJ) coupling and mitochondrial dysfunction are important features of CH, but the mechanisms of decreased coupling and energy impairment are poorly understood. It has been reported that GJA1-20k has a strong tropism for mitochondria and is required for the trafficking of connexin 43 (Cx43) to cell–cell borders. In this study, we investigated the effects of GJA1-20k on Cx43 GJ coupling and mitochondrial function in the pathogenesis of CH. We performed hematoxylin–eosin (HE) and Masson staining, and observed significant CH in 18-week-old male spontaneously hypertensive rats (SHRs) compared to age-matched normotensive Wistar-Kyoto (WKY) rats. In cardiomyocytes from SHRs, the levels of Cx43 at the intercalated disc (ID) and the expression of GJA1-20k were significantly reduced, whereas JAK-STAT signaling was activated. Furthermore, the SHR rats displayed suppressed mitochondrial GJA1-20k and mitochondrial biogenesis. Administration of valsartan (10 mg· \({\rm{kg}}^{-1_{.}}\) d−1, i.g., for 8 weeks) prevented all of these changes. In neonatal rat cardiomyocytes (NRCMs), overexpression of GJA1-20k attenuated Ang II-induced cardiomyocyte hypertrophy and caused elevated levels of GJ coupling at the cell–cell borders. Pretreatment of NRCMs with the Jak2 inhibitor AG490 (10 µM) blocked Ang II-induced reduction in GJA1-20k expression and Cx43 gap junction formation; knockdown of Jak2 in NRCMs significantly lessened Ang II-induced cardiomyocyte hypertrophy and normalized GJA1-20k expression and Cx43 gap junction formation. Overexpression of GJA1-20k improved mitochondrial membrane potential and respiration and lowered ROS production in Ang II-induced cardiomyocyte hypertrophy. These results demonstrate the importance of GJA1-20k in regulating gap junction formation and mitochondrial function in Ang II-induced cardiomyocyte hypertrophy, thus providing a novel therapeutic strategy for patients with cardiomyocyte hypertrophy.

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This work was supported by the National Natural Science Foundation of China (grant No. 81473234), the Joint Fund of the National Natural Science Foundation of China (grant No. U1303221), the Guangdong Basic and Applied Basic Research Foundation (grant No. 2019A1515012215), and a grant from the Department of Science and Technology of Guangdong Province (grant No. 20160908).

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LT and QW conceived and designed the study. YLF and FHP performed the siRNA and cDNA transfection experiments, qPCR and Western blot analyses. NZZ and QL performed the flow cytometry experiments and immunofluorescence and collected and analyzed the data. SYC was involved in cell culture and made substantial contributions to the acquisition and interpretation of the data. YLF wrote the manuscript. LT and QW revised and amended the draft. QW contributed to the final approval of the version to be published. All authors read and approved the final manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy and integrity of all parts of the work are appropriately investigated and resolved.

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Correspondence to Qin Wang.

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The authors declare no competing interests.

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Fu, Yl., Tao, L., Peng, Fh. et al. GJA1-20k attenuates Ang II-induced pathological cardiac hypertrophy by regulating gap junction formation and mitochondrial function. Acta Pharmacol Sin 42, 536–549 (2021).

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  • cardiac hypertrophy
  • gap junctions
  • GJA1-20k
  • mitochondria
  • angiotensin II

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