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<p>Cardioprotective effect of cold acclimation (5&#xa0;weeks; 9&#xa0;°C; CA) and the same effect persisting 2&#xa0;weeks after recovery from CA (CAR) are induced by different mechanisms. We showed that salvage β<sub>2</sub>-adrenoceptor/G<sub>i</sub>/Akt pathway is only involved in the mechanism of cardioprotection after CAR. Since the mechanism of CA-elicited cardioprotection is not known, we examined the role of JAK2/STAT3 pathway. Male Wistar rats exposed to CA and controls (24&#xa0;°C) were treated with the JAK2 inhibitor AG490 affecting downstream STAT3 signaling in the heart (5&#xa0;mg/kg/day) for three days prior to the end of experiment. AG490 administration abolished CA-elicited reduction of infarct-size and significant improvement of MPT pore opening. IL-6, as the main STAT3 upstream effector, was upregulated by CA, and AG490 reversed its level. CA had no effect on IL-1β and TNF-α, but was upregulated by AG490 in controls, and downregulated in CA-AG490 group. CA also reduced pro-apoptotic p38-MAPK, which was abolished by AG490 administration. Spatial expression analyses revealed CA-elicited translocation of total-STAT3 from mitochondria to sarcolemma compartment which was eliminated by JAK2/STAT3 inhibition. However, CA-induced loss of pSTAT3<sup>Y705</sup> from sarcolemma compartment, and loss of pSTAT3<sup>S727</sup> from nucleus. These results identify non-genomic, mitochondria-associated STAT3 activity as a confirmed mechanism of CA-elicited cardioprotection.</p>

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Causal relevance of the JAK/STAT pathway for cardioprotection via cold acclimation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Petr Kasik,
  • Frantisek Galatik,
  • Petr Matous,
  • Petr Paral,
  • Daniel Vasek,
  • Daniela Horníkova,
  • Barbara Elsnicova,
  • Jitka M. Zurmanova

摘要

Cardioprotective effect of cold acclimation (5 weeks; 9 °C; CA) and the same effect persisting 2 weeks after recovery from CA (CAR) are induced by different mechanisms. We showed that salvage β2-adrenoceptor/Gi/Akt pathway is only involved in the mechanism of cardioprotection after CAR. Since the mechanism of CA-elicited cardioprotection is not known, we examined the role of JAK2/STAT3 pathway. Male Wistar rats exposed to CA and controls (24 °C) were treated with the JAK2 inhibitor AG490 affecting downstream STAT3 signaling in the heart (5 mg/kg/day) for three days prior to the end of experiment. AG490 administration abolished CA-elicited reduction of infarct-size and significant improvement of MPT pore opening. IL-6, as the main STAT3 upstream effector, was upregulated by CA, and AG490 reversed its level. CA had no effect on IL-1β and TNF-α, but was upregulated by AG490 in controls, and downregulated in CA-AG490 group. CA also reduced pro-apoptotic p38-MAPK, which was abolished by AG490 administration. Spatial expression analyses revealed CA-elicited translocation of total-STAT3 from mitochondria to sarcolemma compartment which was eliminated by JAK2/STAT3 inhibition. However, CA-induced loss of pSTAT3Y705 from sarcolemma compartment, and loss of pSTAT3S727 from nucleus. These results identify non-genomic, mitochondria-associated STAT3 activity as a confirmed mechanism of CA-elicited cardioprotection.