Recent studies have shown that myocardial ischemia/reperfusion (I/R)-induced necrosis can be controlled by multiple genes. In this study, we observed that both strands (5p and 3p) of miR-223 were remarkably dysregulated in mouse hearts upon I/R. Precursor miR-223 (pre-miR-223) transgenic mouse hearts exhibited better recovery of contractile performance over reperfusion period and lesser degree of myocardial necrosis than wild type hearts upon ex vivo and in vivo myocardial ischemia. Conversely, pre-miR-223 knock-out (KO) mouse hearts displayed opposite effects. Furthermore, we found that the RIP1/RIP3/MLKL necroptotic pathway and inflammatory response were suppressed in transgenic hearts, whereas they were activated in pre-miR-223 KO hearts upon I/R compared with wild type controls. Accordingly, treatment of pre-miR-223 KO mice with necrostatin-1s, a potent necroptosis inhibitor, significantly decreased I/R-triggered cardiac necroptosis, infarction size, and dysfunction. Mechanistically, we identified two critical cell death receptors, TNFR1 and DR6, as direct targets of miR-223-5p, whereas miR-223-3p directly suppressed the expression of NLRP3 and IκB kinase α, two important mediators known to be involved in I/R-induced inflammation and cell necroptosis. Our findings indicate that miR-223-5p/-3p duplex works together and cooperatively inhibits I/R-induced cardiac necroptosis at multiple layers. Thus, pre-miR-223 may constitute a new therapeutic agent for the treatment of ischemic heart disease.

Invasive coronary angiography imposes risks and high medical costs. Therefore, accurate, reliable, non-invasive, and cost-effective methods for diagnosing coronary stenosis are required. We designed a machine learning-based risk-prediction system as an accurate, noninvasive, and cost-effective alternative method for evaluating suspected coronary heart disease (CHD) patients. Electronic medical record data were collected from suspected CHD patients undergoing coronary angiography between May 1, 2017, and December 31, 2019. Multi-Class XGBoost, LightGBM, Random Forest, NGBoost, logistic models and MLP were constructed to identify patients with normal coronary arteries (class 0: no coronary artery stenosis), minimum coronary artery stenosis (class 1: 0 < stenosis <50%), and CHD (class 2: stenosis ≥50%). Model stability was verified externally. A risk-assessment and management system was established for patient-specific intervention guidance. Of 1577 suspected CHD patients, 81 (5.14%) had normal coronary arteries. The XGBoost model demonstrated the best overall classification performance (micro-average receiver operating characteristic [ROC] curve: 0.92, macro-average ROC curve: 0.89, class 0 ROC curve: 0.88, class 1 ROC curve: 0.90, class 2 ROC curve: 0.89), with good external verification. In class-specific classification, the XGBoost model yielded F1 values of 0.636, 0.850, and 0.858, for Classes 0, 1, and 2, respectively. The visualization system allowed disease diagnosis and probability estimation, and identified the intervention focus for individual patients. Thus, the system distinguished coronary artery stenosis well in suspected CHD patients. Personalized probability curves provide individualized intervention guidance. This may reduce the number of invasive inspections in negative patients, while facilitating decision-making regarding appropriate medical intervention, improving patient prognosis.

Recent evidence suggests that elevated plasma levels of Trimethylamine-N-oxide (TMAO) can prolong the duration of elevated blood pressure in rats. The purpose of this study was to investigate the plasma TMAO level in Spontaneously Hypertensive Rats (SHR) and to explore the possible relationship between TMAO and aquaporin-2 (AQP-2) in the formation of hypertension. Twelve-week-old, male Spontaneously Hypertensive rats (SHR, n = 40) and Wistar-Kyoto rats (WKY, n = 40) were accordingly grouped into SHR group and WKY group. Each group was divided randomly into four subgroups: Untreated group, TMAO group, TMAO+Tolvaptan (TMAO+TVP) group, and TVP group, respectively. Systolic blood pressure (SBP), plasma TMAO, plasma osmolality (POsm), plasma vasopressin (PAVP), and plasma AQP-2 (PAQP-2) concentration were measured, and the expression of AQP-2 in kidney medulla was detected by RT-PCR and Western blot. At 14 weeks, rats in SHR TMAO group were shown the increased plasma TMAO, POsm, PAVP, and PAQP-2 levels, while those rats in SHR TMAO+TVP group were shown the decreased plasma TMAO, POsm, and PAQP-2 levels, but an even higher PAVP (due to the blockage of TVP to V2 receptor). These findings indicate that an increase of plasma TMAO levels in SHR leads to a higher plasma osmotic pressure, triggers the regulation of the TMAO-AVP-AQP-2 axis in SHR, elicits the greater water reabsorption, and eventually leads to hypertension.

Cardiac hypertrophy mainly predicts heart failure and is highly linked with sudden loss of lives. MicroRNAs (miRNAs) play essential roles in the development of cardiac hypertrophy through binding to corresponding mRNA targets. In this study, in order to investigate the roles of two mature forms of miRNA-195, miR-195-3p, and miR-195-5p, in vitro and in vivo models of cardiac hypertrophy were established by applying angiotensin II (Ang II) to H9c2 cardiomyocytes and infusing chronic Ang II to mice, respectively. We found that miR-195-5p was evidently equally upregulated in the in vitro and in vivo studies of cardiac hypertrophy induced by Ang II. High expressed miR-195-5p could adequately promote hypertrophy, whereas the suppression of miR-195-5p prevented hypertrophy of H9c2 cardiomyocytes under Ang II treatment. Furthermore, the luciferase reporter system demonstrated that MFN2 and FBWX7 were target genes of miR-195-5p, which negatively regulated the expression of these two genes in H9c2 cells. By contrast, in both models, expression of miR-195-3p was only slightly changed without statistical significance. In addition, we observed a trend towards decreased expression of hypertrophic markers by overexpressing miR-195-3p in AngII-treated H9c2 cardiomyocytes in vitro. Taken together, our study indicates that miR-195-5p promotes cardiac hypertrophy via targeting MFN2 and FBXW7 and may provide promising therapeutic strategies for interfering cardiac hypertrophy.

Leukotriene B4 (LTB4)-mediated leukocyte recruitment and inflammatory cytokine production make crucial contributions to chronic inflammation and sepsis; however, the role of LTB4 in lipopolysaccharide (LPS)-induced cardiac dysfunction remains unclear. Therefore, the present study addressed this issue using an LTB4 receptor 1 (BLT1) inhibitor. Administration of LPS to mice resulted in decreased cardiovascular function. Inhibition of LTB4/BLT1 with the BLT1 inhibitor U75302 significantly improved survival and attenuated the LPS-induced acute cardiac dysfunction. During LPS challenge, the phosphorylated AMPK/ACC signaling pathway was slightly activated, and this effect was enhanced by U75302. Additionally, pNF-κB, Bax and cleaved caspase-3 were upregulated by LPS, and Bcl-2, IκB-α, mitochondrial complex I, complex II, and OPA1 were downregulated; however, these effects were reversed by U75302. The results indicated that the BLT1 antagonist suppressed cardiac apoptosis, inflammation, and mitochondrial impairment. Furthermore, the protection provided by the BLT1 inhibitor against LPS-induced cardiac dysfunction was significantly reversed by the AMPK inhibitor Compound C. In conclusion, inhibiting the LTB4/BLT1 signaling pathway via AMPK activation is a potential treatment strategy for septic cardiac dysfunction because it efficiently attenuates cardiac apoptosis, which may occur via the inhibition of inflammation and mitochondrial dysfunction.