Podoplanin-positive cell-derived small extracellular vesicles contribute to cardiac amyloidosis after myocardial infarction

AUTHORS

Maria Cimini, Ulrich H.E. Hansmann, Carolina Gonzalez, Andrew D. Chesney, May M. Truongcao, Erhe Gao, Tao Wang, Rajika Roy, Elvira Forte, Vandana Mallaredy, Charan Thej, Ajit Magadum, Darukeshwara Joladarashi, Cindy Benedict, Water J. Koch, Çağla Tükel, Raj Kishore

ABSTRACT

Cardiac amyloidosis is a secondary phenomenon of an already pre-existing chronic condition. Whether cardiac amyloidosis represents one of the complications post myocardial infarction (MI) has yet to be fully understood. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived serum amyloid A 3 (SAA3) monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from cardiac stromal cells (CSCs), which, in response to MI, activate the expression of a platelet aggregation-inducing type I transmembrane glycoprotein, Podoplanin (PDPN). CSCPDPN+-derived small extracellular vesicles (sEVs) are enriched in SAA3, and exosomal SAA3 engages with macrophage by Toll-like receptor 2, triggering overproduction with consequent impaired clearance and aggregation of SAA3 monomers into rigid fibers. SAA3 amyloid deposits reduce cardiac contractility and increase scar stiffness. Inhibition of SAA3 aggregation by retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils and improves heart function post MI.

Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1

AUTHORS

Bin Li, Wen-Wu Bai, Tao Guo, Zhen-Yu Tang, Xue-Jiao Jing, Ti-Chao Shan, Sen Yin, Ying Li, Fu Wang, Mo-Li Zhu, Jun-Xiu Lu, Yong-Ping Bai, Bo Dong, Peng Li & Shuang-Xi Wang

ABSTRACT

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

Sex differences in the incidence and mode of death in rats with heart failure with preserved ejection fraction

AUTHORS

Khaled Elkholey, Lynsie Morris, Monika Niewiadomska, Jeremy Houser, Michelle Ramirez, Mulan Tang, Mary Beth Humphrey, Stavros Stavrakis

ABSTRACT

Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure, and sudden death is the leading cause of mortality. We aimed to explore sex differences in outcomes in rats with HFpEF and sought to identify the underlying mechanisms. Dahl salt-sensitive rats of either sex were randomized into high-salt diet (HS diet; 8% NaCl, n = 46, 50% female) or low-salt diet (LS diet; 0.3% NaCl; n = 24, 50% female) at 7 weeks of age. After 6 and 10 weeks of LS or HS diets, the ECG, heart rate variability, cytokines and echocardiographic parameters were measured. The animals were monitored daily for development of HFpEF and survival. Over 6 weeks of HS diet, rats developed significant hypertension and signs of HFpEF. Compared with female HS diet-fed rats, males exhibited more left ventricular dilatation, a longer QT interval, and worse autonomic tone, as assessed by heart rate variability and elevated inflammatory cytokines. Ten of 23 (46%) male rats died during follow-up, compared with two of 23 (9%) female rats (P = 0.01). There were four sudden deaths in males (with ventricular tachycardia documented in one rat), whereas the females died of heart failure. In conclusion, male rats with HFpEF exhibit worse survival compared with females and are at a higher risk for sudden death, attributable in part to QT prolongation, autonomic dysregulation and enhanced inflammation. These data might provide the basis for the development of sex-specific interventions in HFpEF targeting these abnormalities.