Excess ischemic tachyarrhythmias trigger protection against myocardial infarction in hypertensive rats

Author:

Neckář Jan12ORCID,Alánová Petra1,Olejníčková Veronika13,Papoušek František1,Hejnová Lucie4,Šilhavý Jan5,Behuliak Michal6,Bencze Michal6,Hrdlička Jaroslav1,Vecka Marek7,Jarkovská Dagmar8,Švíglerová Jitka8,Mistrová Eliška8,Štengl Milan8,Novotný Jiří4,Ošťádal Bohuslav1,Pravenec Michal5,Kolář František1

Affiliation:

1. Laboratory of Developmental Cardiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic

2. Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

3. Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic

4. Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic

5. Laboratory of Genetics of Model Diseases, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic

6. Laboratory of Experimental Hypertension, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic

7. 4th Department of Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic

8. Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic

Abstract

Abstract Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion.

Publisher

Portland Press Ltd.

Subject

General Medicine

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