Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs.

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/ß5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.

Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent activation of the AMPK-ULK1 pathway.

In hypertrophic hearts, autophagic flux insufficiency is recognized as a key pathology leading to maladaptive cardiac remodeling and heart failure. This study aimed to illuminate the cardioprotective role and mechanisms of a new myokine and adipokine, irisin, in cardiac hypertrophy and remodeling. Adult male wild-type, mouse-FNDC5 (irisin-precursor)-knockout and FNDC5 transgenic mice received 4 weeks of transverse aortic constriction (TAC) alone or combined with intraperitoneal injection of chloroquine diphosphate (CQ). Endogenous FNDC5 ablation aggravated and exogenous FNDC5 overexpression attenuated the TAC-induced hypertrophic damage in the heart, which was comparable to the protection of irisin against cardiomyocyte hypertrophy induced by angiotensin II (Ang II) or phenylephrine (PE). Accumulated autophagosome and impaired autophagy flux occurred in the TAC-treated myocardium and Ang II- or PE-insulted cardiomyocytes. Irisin deficiency caused reduced autophagy and aggravated autophagy flux failure, whereas irisin overexpression or supplementation induced protective autophagy and improved autophagy flux, which were reversed by autophagy inhibitors Atg5 siRNA, 3-MA and CQ. Irisin boosted the activity of only AMPK but not Akt and MAPK family members in hypertrophic hearts and cultured cardiomyocytes and further activated ULK1 at Ser555 but not Ser757 and did not affect the mTOR-S6K axis. Blockage of AMPK and ULK1 with compund C and SBI-0206965, respectively, both abrogated irisin's protection against cardiomyocyte hypertrophic injury and reversed its induction of both autophagy and autophagy flux. Our results suggest that irisin protects against pressure overload-induced cardiac hypertrophy by inducing protective autophagy and autophagy flux via activating AMPK-ULK1 signaling.

[Quantitative Measurements on the Blood Flow Fields of Left Atrial Appendage using Vector Flow Mapping in Patients with Nonvalvular Atrial Fibrillation].

OBJECTIVE: To quantify the hemodynamic characteristics of patients with nonvalvular atrial fibrillation. METHODS: Twenty patients with paroxysmal atrial fibrillation and 15 patients with persistent atrial fibrillation enrolled in this study,while 12 patients with sinus rhythms served as controls. The hemodynamic characteristics of the patients in left atrial appendage were measured by transesophageal echocardiography (TEE) and vector flow mapping (VFM) using indicators such as vectors,vortex and energy loss (EL). RESULTS: ① Significant differences appeared between the patients with atrial fibrillation and the controls in heart rate,size of left atrium,size of left atrial appendage (LAA),and velocities of LAA filling and emptying. ② Regular vectors in LAA in early systole and late diastole were found in the patients with paroxysmal atrial fibrillation and the controls; whereas,irregular vectors with direction alternating were visualized in the whole cardiac cycle in the patients with persistent atrial fibrillation. ③ Small vortexes were observed at the opening of the left atrial appendage in late diastole in the patients with paroxysmal atrial fibrillation and the controls. ④ Peak EL values occurred in early systole and late diastole in the patients with paroxysmal atrial fibrillation and the controls. But the patients with persistent atrial fibrillation had increased EL values over the whole cardiac cycle. CONCLUSION: VFM can visualize and quantify the hemodynamics of LAA in patients with different heart rhythms. It may provide a new method for assessing atrial fibrillation.

[Application of Echocardiography to Support Transapical Transcatheter Aortic Valve Implantation in Patients with Aortic Regurgitation].

OBJECTIVE: To explore the role of echocardiography in pre-procedural,peri-procedural and post-procedural stages of transapical transcatheter aortic valve implantation (TAVI) in patients with aortic regurgitation (AR). METHODS: 31 patients with pure/dominant AR at a high risk on surgery were enrolled in this study. The degree of their aortic regurgitation was evaluated before TAVI,as well as the related diameters of aortic root and the left ventricular systolic function measured by transthoracic echocardiography (TTE). TEE was used to reevaluate the valve pathology after general anesthesia. TEE in combination with fluoroscopy provided accurate position of the prosthetic valve for implantation. TEE was also used to monitor complications and to evaluate immediate post-procedure paravalvular regurgitation. The post TAVI follow-up included valve heamodynamic status,complications,left ventricular systolic function and left ventricular mass index (LVMI) measured by TEE. RESULTS: Transapical TAVI was successful in 29 of the 31 patients: 23 experienced no or little paravalvular regurgitation; 6 had mild paravalvular regurgitation. The left ventricular end-diastolic diameter (LVDd) and left ventricular mass index (LVMI) of the patients decreased significantly one week after TAVI,which progressed until one month later ( P<0.05) . The left ventricular ejection (EF) of the patients also decreased one week after TAVI ( P<0.05) ,but it resumed to the pre-procedural level one month later. CONCLUSION: Transapical TAVI is a potentially safe and effective therapy for patients with pure/dominant AR at a high risk on open-heart surgery. Echocardiography plays an important role in pre-procedural evaluation,peri-procedural monitoring and post-procedural follow-up in TAVI.