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All anthracyclines, including doxorubicin (DOXO), the most common and still indispensable drug, exhibit cardiotoxicity with inherent risk of irreversible cardiomyopathy leading to heart failure with reduced ejection fraction (HFrEF). Current pharmacological strategies are clearly less effective for this type of HFrEF, hence an urgent need for new therapeutic approaches. The prerequisite for success is thorough understanding of pathophysiology of this HFrEF form, which requires an appropriate animal model of the disease. The aim of this study was to comprehensively characterise a novel model of HF with cardiorenal syndrome, i.e. DOXO-induced HFrEF with nephrotic syndrome, in which DOXO was administered to Ren-2 transgenic rats (TGR) via five intravenous injections in a cumulative dose of 10 mg/kg of body weight (BW). Our analysis included survival, echocardiography, as well as histological examination of the heart and kidneys, blood pressure, but also a broad spectrum of biomarkers to evaluate cardiac remodelling, fibrosis, apoptosis, oxidative stress and more. We have shown that the new model adequately mimics the cardiac remodelling described as "eccentric chamber atrophy" and myocardial damage typical for DOXO-related cardiotoxicity, without major damage of the peritoneum, lungs and liver. This pattern corresponds well to a clinical situation of cancer patients receiving anthracyclines, where HF develops with some delay after the anticancer therapy. Therefore, this study may serve as a comprehensive reference for all types of research on DOXO-related cardiotoxicity, proving especially useful in the search for new therapeutic strategies., (© 2024. The Author(s).)

Objective: We examined if renal denervation (RDN) attenuates the progression of aortocaval fistula (ACF)-induced heart failure or improves renal hemodynamics in Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension., Methods: Bilateral RDN was performed 1 week after creation of ACF. The animals studied were ACF TGR and sham-operated controls, and both groups were subjected to RDN or sham denervation. In separate groups, renal artery blood flow (RBF) responses were determined to intrarenal ANG II (2 and 8 ng), norepinephrine (NE) (20 and 40 ng) and acetylcholine (Ach) (10 and 40 ng) 3 weeks after ACF creation., Results: In nondenervated ACF TGR, the final survival rate was 10 versus 50% in RDN rats. RBF was significantly lower in ACF TGR than in sham-operated TGR (6.2 ± 0.3 vs. 9.7 ± 0.5 mL min-1 g-1, p < 0.05), the levels unaffected by RDN. Both doses of ANG II decreased RBF more in ACF TGR than in sham-operated TGR (-19 ± 3 vs. -9 ± 2% and -47 ± 3 vs. -22 ± 2%, p < 0.05 in both cases). RDN did not alter RBF responses to the lower dose, but increased it to the higher dose of ANG II in sham-operated as well as in ACF TGR. NE comparably decreased RBF in ACF TGR and sham-operated TGR, and RDN increased RBF responsiveness. Intrarenal Ach increased RBF significantly more in ACF TGR than in sham-operated TGR (29 ± 3 vs. 17 ± 3%, p < 0.05), the changes unaffected by RDN. ACF creation induced marked bilateral cardiac hypertrophy and lung congestion, both attenuated by RDN. In sham-operated but not in ACF TGR, RDN significantly decreased mean arterial pressure., Conclusion: The results show that RDN significantly improved survival rate in ACF TGR; however, this beneficial effect was not associated with improvement of reduced RBF or with attenuation of exaggerated renal vascular responsiveness to ANG II., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

While necroptosis has been shown to contribute to the pathogenesis of post-infarction heart failure (HF), the role of autophagy remains unclear. Likewise, linkage between these two cell death modalities has not been sufficiently investigated. HF was induced by 60-min left coronary occlusion in adult Wistar rats and heart function was assessed 6 weeks later followed by immunoblotting analysis of necroptotic and autophagic proteins in both the left (LV) and right ventricle (RV). HF had no effect on RIP1 and RIP3 expression. PhosphoSer229-RIP3, acting as a pro-necroptotic signal, was increased in LV while deceased in RV of failing hearts. Total MLKL was elevated in RV only. Decrease in pSer555-ULK1, increase in pSer473-Akt and no significant elevation in beclin-1 and LC3-II/I ratio indicated rather a lowered rate of autophagy in LV. No beclin-1 upregulation and decreased LC3 processing also suggested the inhibition of both autophagosome formation and maturation in RV of failing hearts. In contrast, p89 PARP1 fragment, a marker of executed apoptosis, was increased in RV only. This is the first study showing a different signaling in ventricles of the late phase of post-infarction HF, highlighting necroptosis itself rather than its linkage with autophagy in LV, and apoptosis in RV.

Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1β axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background/aims: We found recently that the aortocaval fistula (ACF)-induced heart failure (HF) results in higher mortality in female than in male rats. Possibly, the development of renal dysfunction in the females, unlike in males, is associated with altered renal vascular responsiveness to angiotensin II (ANG II)., Methods: Five or 20 weeks after ACF creation (compensated and decompensated HF, respectively), we assessed renal blood flow (RBF) responses to intrarenal administration of ANG II, norepinephrine (NE), and acetylcholine (Ach) in female ACF and sham-operated rats., Results: In ACF females, ANG II decreased RBF more than in healthy animals, unlike with earlier published data in male ACF rats that responded similarly. Also, NE decreased RBF more in female ACF rats, whereas Ach increased RBF to the same extent in female ACF and sham-operated rats. RBF responses to intravenous administration of NE and Ach were almost identical in female and male ACF rats., Conclusion: Female ACF rats studied at the onset of HF decompensation reveal, in contrast to male rats, enhanced renal vascular responsiveness to both NE and ANG II. When associated with the demonstrated increased intrarenal ANG II and NE concentrations, such hyperresponsiveness might promote the development of renal dysfunction and accelerate HF decompensation., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Objective: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs)., Methods: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation)., Results: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR., Conclusion: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Adaptation to continuous normobaric hypoxia (CNH) protects the heart against ischemia/reperfusion injury but much less is known about its potential therapeutic effects. The aim of this study was to find out whether post-infarction exposure to CNH can attenuate the progression of heart failure. Ten-week-old male rats underwent myocardial infarction (MI) or sham operation. MI was induced by 60-min coronary artery occlusion. Seven days post-MI, the rats were randomly assigned to two groups: i) sedentary controls kept at room air and ii) rats exposed to CNH (12 % O(2), 3 weeks). Echocardiographic examination of the left ventricle (LV) was performed 3 days before surgery and 7, 14 and 28 days post-MI. MI resulted in a gradual increase in LV end-diastolic diameter (LVD(d)) compared to sham-operated animals. Fractional shortening (FS) decreased from 42.8 % before MI to 15.1 % on day 28 post-MI. CNH significantly attenuated ventricular dilatation without affecting scar area and FS. Our data suggest that prolonged exposure to CNH has certain potential to attenuate the progression of unfavorable changes in ventricular geometry induced by MI in rats.