Book of Abstracts - New Frontiers 2022

Abstracts of oral presentations

MILD COLD ACCLIMATION AS A NEW CARDIOPROTECTIVE INTERVENTION

J. Žurmanová 1 , A. Marvanová 1 , V. Tibenská 1 , P. Kšík 1 , A. Žbírková 1 , B. Elsnicová 1 , L. Hejnová 1 , D. Horníková 1 , P. Vodička 2 , J. Novotný 1 , B. Szeiffová Bačová 3 , M. Sýkora 3 , N. Tribulová 3 , F. Kolář 4 , O. Nováková 1,4 1 Faculty of Science, Charles University, Prague, Czech Republic; 2 Institute of Animal Physiology and Genetics, Czech Academy of Sciences v.v.i., Libechov, Czech Republic; 3 Researcher at Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia; 4 Institute of Physiology, Czech Academy of Sciences v.v.i., Prague, Czech Republic Despite the progress in research and therapy, ischemic heart disease remains the most common cause of death and comorbidity worldwide. Moreover, many promising targets that have been demonstrated in animal models have failed in clinical trials (1). Recently, we demonstrated a unique cardioprotective model of mild cold acclimation (CA, 8±1 ºC, 5 weeks) that reduced the extent of myocardial infarction, improved mitochondrial resistance to Ca 2+ -overload, and persisted for another 2 weeks after recovery (CAR). Under these conditions, the negative side effects such as hypertension and hypertrophy were excluded(2,3) as the temperature was set just below the threshold of shivering thermogenesis in rats and below the threshold of cold- induced hypertension (4). Three subtypes of β - adrenergic receptors (β -ARs) are expressed in the left ventr icular myocardium in the following ratio: β1 - ARs (~70%), β2 - ARs (~27%), and β3 -ARs (~3%). All three β - ARs can activate Gαs. β1 -ARs are only coupled to the stimulatory G protein (Gs) and are required for hormone-stimulated cAMP generation by adenylyl cyclase. The major target protein stimulated by cAMP is cAMP-dependent protein kinase A (PKA). We found that the CA-elicited cardioprotective phenotype is not sensitive to metoprolol administration, preserves the function of adenylyl cyclase signalling and the p otential role lies in the upregulated β2/β3 -AR pathways. Further study revealed the cardioprotective effect of CA and that persisting for 2 weeks CAR engages in different mechanisms. The inhibitory Giα1/2 and Giα3 proteins were upregulated and the protein kinase B(Akt) was activated only in the CAR group. Acute administration of β2 -AR inhibitor ICI-118551 abolished the protective effect in the CAR group but had no effect in the control and CA groups. Then we wondered, what is the shortest time of the cold exposure to achieve an improvement in cardiac ischemic tolerance. Based on preliminary data, we chose 1-3-10 days of the cold exposure and characterized the time course of brown adipose tissue activation (mitochondrial biogenesis, AMPK activation, UCP1, and FGF21 levels), inflammatory markers, and myocardial responses at physiological and cellular levels to determine the principle of cold-elicited cardioprotection at the early stages of the acclimation. References

1. Paradies et al. doi.org/10.1007/978-981-13-1114-7_22. 2. Tibenska V et al. doi: 10.1152/japplphysiol.00511.2019. 3. Tibenská V. et al.. doi: 10.1152/japplphysiol.00756.2020. 4. Lømo et al., Njå, Acta Physiol. 228, 1– 26 (2020).

Keywords: cardioprotection, mild cold acclimation, adrenergic signalling

Funding:This work has been supported by the Charles University Grant Agency (GAUK 641216), Czech Science Foundation (17-07748S), and the Ministry of Education, Youth and Sport of the Czech Republic (SVV-260571/2020). Microscopy was performed in the Laboratory of Confocal and Fluorescence Microscopy cofinanced by the European Regional Development Fund and the state budget of the Czech Republic, Project No. CZ.1.05/4.1.00/16.0347 and CZ.2.16/3.1.00/21515.

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