ABSTRACT
Heart failure is the leading cardiovascular comorbidity in chronic kidney disease (CKD) patients. Among the types of heart failure according to ejection fraction, heart failure with preserved ejection fraction (HFpEF) is the most common type of heart failure in CKD patients. However, the specific animal model of HFpEF afer CKD is currently missing. In this study, we determined the heart failure characteristics and dynamic progression in CKD mice. Based on these features, we established the practical HFpEF after CKD mouse model using 5/6 subtotal nephrectomy and retinol administration. Active apoptosis, impaired calcium handling, an imbalance between eNOS and oxidative stress and engaged endoplasmic reticulum stress were observed in our model. RNSseq revealed distinct gene expression patterns between HFpEF after CKD and metabolic induced-HFpEF. Furthermore, we revealed the potential mechanism of the pro-HFpEF effect of retinol. Serum accumulation of retinol in CKD prompts myocardial hypertrophy and fibrosis by activating JAK2 and phosphorylating STAT5. Finally, using small molecule inhibitor AC-4-130, we found STAT5 phosphorylation inhibitor may be a potential intervention target for HFpEF after CKD. In conclusion, we provide a novel animal model and a potential drug target for HFpEF intervention in CKD.
Subject(s)
Heart Failure , Renal Insufficiency, Chronic , Mice , Animals , Heart Failure/drug therapy , Heart Failure/metabolism , Vitamin A/therapeutic use , Vitamin A/metabolism , Janus Kinases/metabolism , STAT5 Transcription Factor/metabolism , Stroke Volume , STAT Transcription Factors/metabolism , Signal Transduction , Disease Models, Animal , Renal Insufficiency, Chronic/drug therapyABSTRACT
Background: This study aimed to verify the effect of soluble guanylate cyclase (sGC) stimulator vericiguat on myocardial ischemia-reperfusion injury and explore its mechanism. Methods: A myocardial ischemia-reperfusion injury model of mice was established and intravenous administration was performed 2 minutes before reperfusion. Triphenyltetrazolium chloride (TTC) staining and echocardiography were used to verify the effect of vericiguat on myocardial ischemia-reperfusion injury in the infarct area, and immunofluorescence was used to observe myocardial pathological changes at different time points after reperfusion. Quantitative proteomics was conducted to analysis the main differentially expressed proteins after drug intervention. The distribution of endothelial cells and sGC after myocardial ischemia-reperfusion injury in mice was observed by immunofluorescence. RNA sequencing of endothelial cells was used to search for differentially expressed molecules. Thioflavin-S staining was used to observe the effect of vericiguat on improving the nonrecurrence phenomenon and reducing the infarct size after reperfusion. Results: The effect of the sGC stimulator vericiguat on myocardial ischemia-reperfusion injury was verified, and myocardial microcirculation significantly increased after drug intervention. Quantitative proteomics found that the protein expression of myocardial tissue in the ischemia-reperfusion area was not significantly different in the drug intervention group, except for increased adenosine triphosphate (ATP) activity. Vericiguat, nitroglycerin, and nitrite did not directly affect apoptosis or cell viability. RNA sequencing of human umbilical vein endothelial cells screened the upregulated antioxidant response. Conclusions: SGC stimulator vericiguat ameliorated myocardial ischemia-reperfusion injury through indirect pathways of improving microcirculation.
ABSTRACT
BACKGROUND: The ketogenic diet (KD) has anti-tumor and anti-diabetic effects in addition to its anti-epileptic role. It could also improve cardiac function and attenuate neurological insult. However, the effect of KD on blood perfusion or tissue recovery after ischemia remains largely unknown. Thus, we observed blood flow and ischemic tissue recovery following hind limb ischemia (HLI) in mice. METHODS: C57 mice were fed with either a KD or normal diet (ND) for 2 weeks, before inducing hind limb ischemia, blood perfusion of ischemic limb tissue was observed at 0, 7, and 21 days post operation. RESULTS: KD not only decreased blood perfusion of ischemic limb tissue but also delayed muscle recovery after ischemia, induced muscle atrophy of non-ischemic tissue compared to mice fed with ND. Furthermore, KD delayed wound healing at the surgical site and aggravated inflammation of the ischemic tissue. At the cellular level, KD altered the metabolic status of limb tissue by decreasing glucose and ketone body utilization while increasing fatty acid oxidation. Following ischemia, glycolysis, ketolysis, and fatty acid utilization in limb tissue were all further reduced by KD, while ketogenesis was mildly increased post KD in this mice model. CONCLUSION: The KD may cause impaired tissue recovery after ischemia and possible muscle atrophy under a prolonged diet. Our results hint that patients with limb ischemia should avoid ketogenic diet.