Heart failure with preserved ejection fraction (HFpEF) accounts for almost half of all heart failure (HF) cases worldwide. Unfortunately, its incidence is expected to continue to rise, and effective therapy to improve clinical outcomes is lacking. Numerous efforts currently directed towards the pathophysiology of human HFpEF are uncovering signal transduction pathways and novel therapeutic targets. The nitric oxide-cyclic guanosine phosphate-protein kinase G (NO-cGMP-PKG) axis has been described as an important regulator of cardiac function. Suppression of the NO-cGMP-PKG signalling pathway is involved in the progression of HFpEF. Therefore, the NO-cGMP-PKG signalling pathway is a potential therapeutic target for HFpEF. In this review, we aim to explore the mechanism of NO-cGMP-PKG in the progression of HFpEF and to summarize potential therapeutic drugs that target this signalling pathway.

High density lipoprotein (HDL) has been proved to be a protective factor for coronary heart disease. Notably, HDL in atherosclerotic plaques can be nitrated (NO2-oxHDL) and chlorinated (Cl-oxHDL) by myeloperoxidase (MPO), likely compromising its cardiovascular protective effects. Here we determined the effects of NO2-oxHDL and Cl-oxHDL on SMC migration using wound healing and transwell assays, proliferation using MTT and BrdU assays, and apoptosis using Annexin-V assay in vitro, as well as on atherosclerotic plaque stability in vivo using a coratid artery collar implantation mice model. Our results showed that native HDL promoted SMC proliferation and migration, whereas NO2-oxHDL and Cl-oxHDL inhibited SMC migration and reduced capacity of stimulating SMC proliferation as well as migration, respectively. OxHDL had no significant influence on SMC apoptosis. In addition, we found that ERK1/2-phosphorylation was significantly lower when SMCs were incubated with NO2-oxHDL and Cl-oxHDL. Furthermore, transwell experiments showed that differences between native HDL, NO2-oxHDL and Cl-oxHDL was abolished after PD98059 (MAPK kinase inhibitor) treatment. In aortic SMCs from scavenger receptor BI (SR-BI) deficient mice, differences between migration of native HDL, NO2-oxHDL and Cl-oxHDL treated SMCs vanished, indicating SR-BI’s possible role in HDL-associated SMC migration. Importantly, NO2-oxHDL and Cl-oxHDL induced neointima formation and reduced SMC positive staining cells in atherosclerotic plaque, resulting in elevated vulnerable index of atherosclerotic plaque. These findings implicate MPO-catalyzed oxidization of HDL may contribute to atherosclerotic plaque instability by inhibiting SMC proliferation and migration through MAPK-ERK pathway which was dependent on SR-BI.

Migration inhibitory factor (MIF) has been shown to be critical in the pathology of early artherosclerosis; this article aim to investigate the plasma levels of MIF in hypertension plus hyperlipidemia patients. A total of 39 hypertension plus hyperlipidemia patients without any previous treatment were enrolled (HTN-HLP). Twenty-five healthy subjects were enrolled as the healthy control group (HEALTHY). Plasma MIF was measured by ELISA; laboratory and clinical characteristics were analyzed. HUVECs were treated with pooled plasma from HTN-HLP and HEALTHY groups, and the protein levels of adhesion molecules VCAM-1 and ICAM-1 were determined by ELISA. We found that plasma MIF was significantly elevated in the HTN-HLP group. Serum NO and eNOS levels were significantly lower; serum ET-1 (endothelin) levels were significantly higher in the HTN-HLP group. Furthermore, blood pressure, baPWV (brachial–ankle pulse wave velocity), and serum ET-1 level were significantly positively; serum NO and eNOS levels were negatively correlated with plasma MIF levels. Plasma from HTN-HLP significantly stimulated VCAM-1 and ICAM-1 protein expression on the surface of HUVECs. Plasma MIF was elevated in HTN-HLP patients and correlates with impaired endothelial function.

Current diagnostic technique in direct identification of multi‐site plaques and simultaneous assessment of plaque vulnerability remains a challenge, which is crucial for indicating the risk of atherosclerotic cardiovascular diseases (ASCVD). Herein, an osteopontin (OPN)‐specific nanoprobe (OPN Ab‐Au/FeNiPO₄@ICG) with both multiple spectra optoacoustic tomography (MSOT) and computed tomography (CT) imaging, is constructed successfully realizing systemic screening of vulnerable plaque. OPN Ab‐Au/FeNiPO₄@ICG nanoprobe specifically targeted OPN‐overexpressed foam cells and recognized the vulnerable plaque at the molecular level. In AS mice, CT imaging exhibits that OPN Ab‐Au/FeNiPO₄@ICG nanoprobe effectively avoid interference from calcification and accurately visualized AS plaque. MSOT functional imaging results reveals that after the injection of OPN Ab‐Au/FeNiPO₄@ICG nanoprobe, the carotid plaque exhibited a much higher MSOT signal than the aortic arch plaque (P = 0.0291). Further pathological analysis displays that the carotid plaque possessed a much higher vulnerability score (P = 0.0247), in agreement with the MSOT signals. More importantly, the linear regression analysis confirms the high correlation between the MSOT signals and plaque vulnerability with R = 0.7095 (P = 0.0216), demonstrating the potential of the proposed nanoprobe in systematic evaluation of plaque vulnerability. This work employs the dual‐model nanoprobe strategy for both plaque localization and vulnerability assessment, greatly advancing the accurate diagnosis of ASCVD.

The present study aimed to investigate the time course of changes in microparticles (MPs) in patients with ST-segment elevation myocardial infarction (STEMI) that underwent percutaneous transluminal coronary intervention (PCI). A total of 24 STEMI patients undergoing primary PCI were enrolled, and circulating MPs were detected immediately prior to and after PCI, and at 4, 24 and 48 h post-PCI. Standard Megamix beads, based measurement protocols, were employed to measure MPs of different cell origin, including endothelial MPs (EMPs), platelet MPs (PMPs) and leukocyte-derived MPs (LMPs), which were identified by CD144, CD41 and CD45, respectively. The results indicated that PMP levels were evidently elevated immediately after PCI, and reached a maximum level at 48 h. In addition, LMP and EMP levels were significantly decreased immediately after the PCI, and then increased gradually with time. The total quantity of the three aforementioned MP types increased gradually at 48 h following PCI. Furthermore, coronary angiographic Gensini scores were significantly positively correlated with the level of PMPs (r2=0.42; P=0.0006). Log-normalized high sensitivity-C-reactive-protein was also significantly correlated with LMPs (r2=0.86; P<0.01). In conclusion, the time course of the changes in circulating MPs of different cell origin, provided information on possible functions of different MPs in STEMI.