ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

Validation of the central blood pressure estimation by the SphygmoCor system in Chinese.

BACKGROUND: Pulse wave analysis using the SphygmoCor system allows the estimation of central blood pressures (BP). However, there is controversy over its accuracy for clinical use. METHODS: In 45 patients undergoing coronary angiography, we compared the ascending aorta BPs measured by the invasive catheter with the estimations by the SphygmoCor system, using paired t-tests, simple correlation analysis, and Bland-Altman plots. RESULTS: The estimation of central systolic BP by SphygmoCor was lower, although statistically insignificant, than that measured by the catheter (144±29 vs. 148±30 mmHg; P=0.98). The standard deviation of the difference amounted to 17 mmHg. Both the measured and estimated central systolic BPs were significantly (P<0.001) lower than the brachial systolic BP (156±30 mmHg). The diastolic BP measured at the brachial artery (87±15 mmHg) and provided by SphygmoCor (90±15 mmHg) were systematically higher (P<0.001) than that measured by the catheter (74±13 mmHg). The SphygmoCor system underestimated the central pulse pressure by -20±14 mmHg compared with the catheter method. The correlation coefficients for systolic BP, diastolic BP, and pulse pressure between catheter measurements and the SphygmoCor estimations were 0.84, 0.60, and 0.82 (P<0.001), respectively. CONCLUSION: When the radial waveform was calibrated with the oscillometric brachial pressures, the SphygmoCor system could not provide accurate estimation of central BPs. The inaccurate measurement of cuff pressure was the major limiting factor for the use of the transfer function in the clinical settings.