- Endothelial TFEB Positively Regulates Post-Ischemic Angiogenesis. [Journal Article]
- CircRCirc Res 2018 Feb 21
- Rationale: Post-ischemic angiogenesis is critical to limit the ischemic tissue damage and improve the blood flow recovery. The regulation and the underlying molecular mechanism...
Rationale: Post-ischemic angiogenesis is critical to limit the ischemic tissue damage and improve the blood flow recovery. The regulation and the underlying molecular mechanisms of post-ischemic angiogenesis are not fully unraveled. Transcription factor-EB (TFEB) is emerging as a master gene for autophagy and lysosome biogenesis. However, the role of TFEB in vascular disease is less understood. Objective: We aimed to determine the role of endothelial TFEB in post-ischemic angiogenesis and its underlying molecular mechanism. Methods and Results: In primary human endothelial cells (ECs), serum starvation induced TFEB nuclear translocation. Vascular endothelial growth factor (VEGF) increased TFEB expression level and nuclear translocation. Utilizing genetically-engineered endothelial cell (EC) specific TFEB transgenic and knockout (KO) mice, we investigated the role of TFEB in post-ischemic angiogenesis in the mouse hind-limb ischemia model. We observed improved blood perfusion and increased capillary density in the EC-specific TFEB transgenic mice compared with the wild-type littermates. Furthermore, blood flow recovery was attenuated in EC-TFEB KO mice compared with control mice. In aortic ring cultures, the TFEB transgene significantly increased vessel sprouting, while TFEB deficiency impaired the vessel sprouting. In vitro, adenovirus-mediated TFEB overexpression promoted EC tube formation, migration and survival whereas small interfering RNA (siRNA)-mediated TFEB knockdown had the opposite effect. Mechanistically, TFEB activated AMP-activated protein kinase (AMPK)-α signaling and upregulated autophagy. Through inactivation of AMPKα or inhibition of autophagy, we demonstrated that the AMPKα and autophagy are necessary for TFEB to regulate angiogenesis in ECs. Finally, the positive effect of TFEB on AMPKα activation and EC tube formation was mediated by TFEB-dependent transcriptional upregulation of MCOLN1. Conclusions: In summary, our data demonstrate that TFEB is a positive regulator of angiogenesis through activation of AMPKα and autophagy, suggesting that TFEB constitutes a novel molecular target for ischemic vascular disease.
- Reflection of Cardioprotection by Remote Ischemic Perconditioning in Attenuated ST-Segment Elevation During Ongoing Coronary Occlusion in Pigs: Evidence for Cardioprotection from Ischemic Injury. [Journal Article]
- CircRCirc Res 2018 Feb 21
- Rationale: Reduction of infarct size (IS) by remote ischemic per-conditioning (perRIC) is evident only after several hours reperfusion. Objective: To develop a potential real...
Rationale: Reduction of infarct size (IS) by remote ischemic per-conditioning (perRIC) is evident only after several hours reperfusion. Objective: To develop a potential real-time estimate of cardioprotection by perRIC we have analyzed the time course of ST-segment elevation. Methods and Results: Anesthetized open-chest pigs were subjected to 60 min coronary occlusion and 180 min reperfusion (placebo; PLA; n=19). perRIC (n=18; 4x5 min/5 min hindlimb occlusion/reperfusion) was induced 20 min after coronary occlusion. Regional myocardial blood flow was measured with microspheres, areas of no-reflow with thioflavin-S, area at risk (AAR) with blue dye, and IS with TTC-staining. Phosphorylation of AKT1/2/3, ERK1/2, and STAT3 was determined by Western blot. ST-segment elevation was analyzed in a V2-like ECG-lead at baseline, 5 and 55 min coronary occlusion, and 10, 30, 60, and 120 min reperfusion. Transmural blood flow at 5 min coronary occlusion was not different between perRIC (0.029±0.015 ml/min/g; mean±SD) and PLA (0.024±0.018 ml/min/g) as was AAR (perRIC: 24±6% of the left ventricle; PLA: 21±4%). Areas of no-reflow tended to be smaller with perRIC (9±12% of AAR vs. 15±14% with PLA; p=0.13). IS with perRIC was 23±12% of AAR vs. 40±11% with PLA (p<0.001). perRIC increased phosphorylation of STAT3 at 120 min reperfusion by 196±142% vs. 109±120% with PLA (p= 0.047). The time courses of ST-segment elevation in perRIC and PLA protocols, respectively, were different (p=0.017). With similar ST-segment elevation at 5 min coronary occlusion (perRIC 282±34 µV; PLA 259±28 µV), partial recovery of ST-segment elevation between 5 and 55 min coronary occlusion was more pronounced with perRIC than PLA (by 111±84 vs. 15±94 µV; p=0.028). Conclusions: IS reduction by perRIC is reflected in the ST-segment elevation during coronary occlusion in pigs, supporting the notion of protection from ischemic injury.
- Specific Activation of the Alternative Cardiac Promoter ofCacna1cby the Mineralocorticoid Receptor. [Journal Article]
- CircRCirc Res 2018 Feb 21
- Rationale: The mineralocorticoid receptor (MR) antagonists belong to the current therapeutic armamentarium for the management of cardiovascular diseases, but the mechanisms con...
Rationale: The mineralocorticoid receptor (MR) antagonists belong to the current therapeutic armamentarium for the management of cardiovascular diseases, but the mechanisms conferring their beneficial effects are poorly understood. Part of the cardiovascular effects of MR are due to the regulation of L-type Cav1.2 Ca2+channel expression, which is generated by tissue-specific alternative promoters as a long 'cardiac' (Cav1.2-LNT) or a short 'vascular' (Cav1.2-SNT) N-terminal transcripts. Objective: To analyze the molecular mechanisms by which aldosterone, through MR, modulates Cav1.2 expression and function in a tissue-specific manner. Methods and Results: In primary cultures of neonatal rat ventricular myocytes, aldosterone exposure for 24 hours increased in a concentration-dependent manner Cav1.2-LNT expression at both mRNA and protein levels, correlating with enhanced concentration-, time- and MR-dependent P1-promoter activity. In silico analysis and mutagenesis identified MR interaction with both specific activating and repressing DNA binding elements on the P1-promoter. The relevance of this regulation is confirmed both ex and in vivo in transgenic mice harboring the luciferase reporter gene under the control of the 'cardiac' P1-promoter. Moreover, we show that this cis-regulatory mechanism is not limited to the heart. Indeed, in smooth muscle cells from different vascular beds, in which the Cav1.2-SNT is normally the major isoform, we found that MR signaling activates 'cardiac' Cav1.2-LNT expression through P1-promoter activation, leading to vascular contractile dysfunction. These results were further corroborated in hypertensive aldosterone-salt rodent models, showing notably a positive correlation between blood pressure and 'cardiac' P1-promoter activity in aorta. This new vascular Cav1.2-LNT molecular signature reduced sensitivity to the Ca2+channel blocker, nifedipine, in aldosterone-treated vessels. Conclusions: Our results reveal that MR acts as a transcription factor to translate aldosterone signal into specific 'cardiac' P1-promoter activation that might influence the therapeutic outcome of cardiovascular diseases.
- Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. [Review]
- CircRCirc Res 2018 Feb 16; 122(4):624-638
- Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated wi...
Heart failure and related morbidity and mortality are increasing at an alarming rate, in large part, because of increases in aging, obesity, and diabetes mellitus. The clinical outcomes associated with heart failure are considerably worse for patients with diabetes mellitus than for those without diabetes mellitus. In people with diabetes mellitus, the presence of myocardial dysfunction in the absence of overt clinical coronary artery disease, valvular disease, and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia, has led to the descriptive terminology, diabetic cardiomyopathy. The prevalence of diabetic cardiomyopathy is increasing in parallel with the increase in diabetes mellitus. Diabetic cardiomyopathy is initially characterized by myocardial fibrosis, dysfunctional remodeling, and associated diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure. Impaired cardiac insulin metabolic signaling, mitochondrial dysfunction, increases in oxidative stress, reduced nitric oxide bioavailability, elevations in advanced glycation end products and collagen-based cardiomyocyte and extracellular matrix stiffness, impaired mitochondrial and cardiomyocyte calcium handling, inflammation, renin-angiotensin-aldosterone system activation, cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and a myriad of cardiac metabolic abnormalities have all been implicated in the development and progression of diabetic cardiomyopathy. Molecular mechanisms linked to the underlying pathophysiological changes include abnormalities in AMP-activated protein kinase, peroxisome proliferator-activated receptors, O-linked N-acetylglucosamine, protein kinase C, microRNA, and exosome pathways. The aim of this review is to provide a contemporary view of these instigators of diabetic cardiomyopathy, as well as mechanistically based strategies for the prevention and treatment of diabetic cardiomyopathy.
- Approaching Regulatory Approval of Cardiovascular Regenerative Therapy. [Journal Article]
- CircRCirc Res 2018 Feb 16; 122(4):552-554
- Recognizing the Top Reviewers of 2017 forCirculation Research. [Journal Article]
- CircRCirc Res 2018 Feb 16; 122(4):551
- David Gutterman: Focusing on the Little Things Leads to Big Discoveries. [Journal Article]
- CircRCirc Res 2018 Feb 16; 122(4):548-550
- Telomere Length Dynamics and Atherosclerotic Disease. [Editorial]
- CircRCirc Res 2018 Feb 16; 122(4):546-547
- Pannexin Channel Inhibition: An Evolving Target to Lower Blood Pressure? [Editorial]
- CircRCirc Res 2018 Feb 16; 122(4):543-545
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- The Cellular Origin of Activated Fibroblasts in the Infarcted and Remodeling Myocardium. [Editorial]
- CircRCirc Res 2018 Feb 16; 122(4):540-542