MFG-E8 facilitates heart repair through M1/M2 polarization after myocardial infarction by inhibiting CaMKII.

BACKGROUND: M1/M2 macrophage polarization affects patient outcomes after myocardial infarction (MI). The relationship between milk fat globule-epidermal growth factor 8 (MFG-E8) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) on macrophage polarization after MI is unknown. To investigate the functional role of MFG-E8 in modulating cardiac M1/M2 macrophage polarization after MI, especially its influence on CaMKII signaling. METHODS: Human ventricular tissue and blood were obtained from patients with MI and controls. MFG-E8-KO mice were constructed (C57BL/6). The mice were randomized to WT-sham, sham-MFG-E8-KO, WT-PBS, rmMFG-E8 (WT injected with rmMFG-E8 10 min after MI), and MFG-E8-KO. The mouse macrophage cell line RAW264.7 was obtained. CaMKII, p-CaMKII, Akt, and NF-κB p65 were determined by qRT-PCR, western blot, and immunofluorescence. RESULTS: The MFG-E8 levels were significantly enhanced after MI in the hearts and plasma of patients with MI compared with controls. The MFG-E8 levels were significantly increased in the hearts and plasma of mice after MI. MFG-E8 was derived from cardiac fibroblasts. The administration of rmMFG-E8 improved ventricular remodeling and cardiac function after MI. rmMFG-E8 did not suppress infiltrating monocyte/macrophages into the peri-infarct area. rmMFG-E8 suppressed the polarization of macrophages to the M1 phenotype and promoted the polarization of macrophages to the M2 phenotype. rmMFG-E8 suppressed CaMKII-dependent signaling in macrophages. CONCLUSIONS: MFG-E8 and CaMKII appear to collaboratively regulate myocardial remodeling and M1/M2 macrophage polarization after MI. These observations suggest new roles for MFG-E8 in inhibiting M1 but promoting M2 macrophage polarization.

Pathological implication of CaMKII in NF-κB pathway and SASP during cardiomyocytes senescence.

Senescence-associated secretory phenotype (SASP) could be developed during heart ageing. But the role of SASP in cardiomyocytes senescence and its molecular mechanism remains undetermined. In this study, we observed elevated Ca2+/calmodulin -dependent protein kinase II (CaMKII) activation in both physiological aged heart and premature senescent cardiomyocytes. Notably, we confirmed the gradual SASP development induced by NF-κB activation in long-term cultured cardiomyocytes. Transgenic inhibition of CaMKII in mice (AC3-I mice) alleviated the NF-κB activation, chronic sterile inflammation and ageing-associated cardiomyopathy. Correspondingly, pharmacological inhibition of CaMKII with KN93 mitigated SASP and hindered cardiomyocytes senescence. Meanwhile, increased NF-κB activation and exacerbated cardiomyocytes senescence were observed with transgenic CaMKII activation. Collectively, our results indicated that the increased CaMKII activation accompanying ageing could aggravate NF-κB activation and SASP development and facilitate cardiomyocytes senescence and heart ageing.

CaMKII inhibition protects against hyperthyroid arrhythmias and adverse myocardial remodeling.

Hyperthyroidism can potentiate arrhythmias and cardiac hypertrophy, whereas Ca2+/calmodulin-dependent kinase II (CaMKII) promotes maladaptive myocardial remodeling. However, it remains unclear whether CaMKII contributes to the progression of hyperthyroid heart disease (HHD). This study demonstrated that CaMKII inhibition can relieve adverse myocardial remodeling and reduce sinus tachycardia, isoproterenol-induced atrial fibrillation, and ventricular arrhythmias in hyperthyroid mice with preserved heart function. Hyperthyroid cardiac hypertrophy was promoted by CaMKII upregulation-induced HDAC4/MEF2a activation. Briefly, CaMKII inhibition benefits HHD management greatly in mice by preventing arrhythmias and maladaptive remodeling.

Identification of a novel pathogenic COL4A3 gene mutation in a Chinese family with autosomal dominant Alport syndrome: A case report.

Alport syndrome (AS) is a genetic disease with various manifestations, including hematuria, proteinuria, impaired renal function and potential ocular or auditory abnormalities. Mutations in the collagen type IV α 3 chain (COL4A3), collagen type IV α 4 chain and collagen type IV α 5 chain genes encoding the α3, α4 and α5 chains of type IV collagen may undermine glomerular basement membrane (GBM) integrity and cause persistent renal deterioration. In the present study, the case of a Chinese family diagnosed with AS was examined. Pedigree investigations and whole exome sequencing (WES) revealed the presence of two heterozygous mutations (c.2603G>A; p.G868E, and c.583G>A; p.G195S) in the COL4A3 gene. p.G868E was identified as the 'culprit' mutation, whereas p.G195S was identified as an 'auxiliary' mutation for AS with regards to the manifestations observed in the patients carrying each of the gene mutations. In conclusion, these findings suggested that c.2603G>A may be a novel overt pathogenic mutation site for autosomal dominant AS. In addition, WES may be effective for the early diagnosis and medical intervention of AS, and may be widely used for AS prognosis prediction and pre-implantation genetic diagnosis.