Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases (CVD). Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants, have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health. First, this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health. We then discuss in detail the signaling pathways mediating exercise’s benefits for cardiovascular health. The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations. The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling. Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects. Moreover, we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD. We also discuss multiple factors that influence exercise’s effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise. We conclude that a deep understanding of the signaling pathways involved in exercise’s benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.

Notoginsenoside R1 (NGR1) is the main monomeric component extracted from the dried roots and rhizomes of Panax notoginseng, and exerts pharmacological action against myocardial infarction (MI). Owing to the differences in compound distribution, absorption, and metabolism in vivo, exploring a more effective drug delivery system with a high therapeutic targeting effect is crucial. In the early stages of MI, CD11b-expressing monocytes and neutrophils accumulate at infarct sites. Thus, we designed a mesoporous silica nanoparticle-conjugated CD11b antibody with loaded NGR1 (MSN-NGR1-CD11b antibody), which allowed NGR1 precise targeted delivery to the heart in a noninvasively manner. By increasing targeting to the injured myocardium, intravenous injection of MSN-NGR1-CD11b antibody nanoparticle in MI mice improved cardiac function and angiogenesis, reduced cell apoptosis, and regulate macrophage phenotype and inflammatory factors and chemokines. In order to further explore the mechanism of NGR1 protecting myocardium, cell oxidative stress model and oxygen-glucose deprivation (OGD) model were established. NGR1 protected H9C2 cells and primary cardiomyocytes against oxidative injury induced by H₂O₂ and OGD treatment. Further network pharmacology and molecular docking analyses suggested that the AKT, MAPK and Hippo signaling pathways were involved in the regulation of NGR1 in myocardial protection. Indeed, NGR1 could elevate the levels of p-Akt and p-ERK, and promote the nuclear translocation of YAP. Furthermore, LY294002 (AKT inhibitor), U0126 (ERK1/2 inhibitor) and Verteporfin (YAP inhibitor) administration in H9C2 cells indicated the involvement of AKT, MAPK and Hippo signaling pathways in NGR1 effects. Meanwhile, MSN-NGR1-CD11b antibody nanoparticles enhanced the activation of AKT and MAPK signaling pathways and the nuclear translocation of YAP at the infarcted site. Our research demonstrated that MSN-NGR1-CD11b antibody nanoparticle injection after MI enhanced the targeting of NGR1 to the infarcted myocardium and improved cardiac function. More importantly, our pioneering research provides a new strategy for targeting drug delivery systems to the ischemic niche.

In heart failure (HF), energy metabolism pathway in cardiac muscle changes from fatty acid β-oxidation to glycolysis. However, the exact mechanism is unknown. Sarcoendoplasmic reticulum Ca²⁺α ATPase (SERCA) expression is downregulated and mitochondrial function is reduced in HF, perhaps partly due to a substantially reduced energy supply for excitation–contraction coupling resulting from a lower fatty acid β-oxidation rate. We investigated whether Astragaloside IV can activate peroxisome proliferator-activated receptor alpha (PPARα) to stimulate fatty acid β-oxidation and increase cardiac energy production, improving mitochondrial function and the efficiency of SERCA in HF. In pressure overload-induced HF mice and isolated hypertrophic myocardial cells, fatty acid β-oxidation and heart function were substantially strengthened following Astragaloside IV treatment, as demonstrated by the increased expression of PPARα and SERCA2a. In vitro, Astragaloside IV regulated energy metabolism by increasing ATP production and enhancing mitochondrial function, attributable to increased oxygen consumption and slightly increased mitochondrial Ca²⁺ uptake. In HF, Astragaloside IV switched glycolysis to fatty acid β-oxidation, as confirmed by reduced anaerobic glycolysis and an increased oxygen consumption ratio. These results suggest that Astragaloside IV can stimulate fatty acid β-oxidation and improve mitochondrial function, which may present a novel cardioprotective treatment that inhibits the progress of HF.

Cardiovascular diseases, the leading cause of death worldwide, are tightly associated with the pathological myocardial fibrosis. Stachydrine (Sta), a major active compound in Chinese motherwort Leonurus heterophyllus, was reported to effectively attenuate cardiac fibrosis, but the cellular and molecular mechanism remains unclear. In this study, the anti-fibrotic effect of Sta and mechanism underlying were explored in a mouse model of pressure overload and AngII stimulated cardiac fibroblasts (CFs). Mice were randomly divided into sham, transverse aorta constriction with saline (TAC+Sal), TAC with telmisartan (TAC+Tel), and TAC with Sta (TAC+Sta) groups. Cardiac morphological and functional changes were evaluated by echocardiography and histological methods, and the molecular alterations were detected by western blotting. Primary cultured neonatal mouse CFs were treated with or without angiotensin II (AngII, 10⁻⁷ M), transformation growth factor β1 (TGFβ1, 10 ng/mL), and different dosage of Sta (10⁻⁶–10⁻⁴ M) for up to 96 h, and cell proliferation, cytotoxicity, morphology and related signals were also detected. The in vivo results revealed that TAC prominently induced cardiac dysfunction, left ventricular dilation, myocardial hypertrophy, and elevated myocardial collagen deposition, accompanied with increased fibrotic markers including α-smooth muscle actin (α-SMA) and periostin. However, Sta treatment partially reversed cardiac morphological and functional deteriorations, and significantly blunted cardiac fibrosis as well as Tel. Increments of myocardial angiotensinogen (AGT), angiotensin converting enzyme (ACE), AngII type 1 receptor (AT1R), and TGFβ1 transcripts, together with increased protein levels of ACE and AngII, after TAC were dramatically down-regulated by Sta treatment. Coincidently, in vitro experiments demonstrated that AngII stimulation in CFs led to up-regulation of AT1R and TGFβ1, and therefore promoted CFs trans-differentiating into hyper-activated myocardial fibroblasts (MFs) as evidenced by increased cell proliferation, collagen and fibrotic makers. On the contrary, Sta potently down-regulated but not directly inhibited AT1R, suppressed TGFβ1 production, and the pro-fibrotic effect of AngII in CFs. Moreover, activation of TGFβ1/Smads signal in the fibrotic process were observed both TAC model and in AngII stimulated CFs, which were also notably blunted by Sta. However, Sta failed to abolish the activation of CFs triggered by TGFβ1. Taken together, it was demonstrated in this study that Sta suppressed ACE/AngII/AT1R-TGFβ1 profibrotic axis, especially on the de novo production of AngII via down-regulating AGT/ACE and AT1R, and therefore inactivated CFs and blunted MFs transition, which ultimately prevented cardiac fibrosis.

The lower cell survival and retention in the hostile microenvironment after transplantation has been implicated as a major bottleneck in the advancement of stem cell therapy for myocardial infarction (MI). In this study, we designed a novel self‐assembling peptide (SAP) by attaching prosurvival peptide QHREDGS derived from angiopoeitin‐1 to the known SAP, RADA16‐I. The mesenchymal stem cells (MSCs) were harvested from male rats and cytoprotective effect of this designer SAP (DSAP) on cultured MSCs was detected by Hoechst 33342 staining after being exposed to oxygen and glucose deprivation (OGD). The cytoprotective effect of MSCs seeded in DSAP (DSAP‐MSCs) on OGD treated cardiomyocytes was examined by TUNEL staining, phosphorylated (p‐) protein kinase B (Akt) level, and ELISA. The therapeutic potential of MSC transplantation carried in DSAP was evaluated in a female rat MI model. PBS, MSCs alone, MSCs seeded in SAP (SAP‐MSCs), or DSAP‐MSCs were transplanted into the border of the infarcted area, respectively. DSAP not only increased the proliferation of MSCs and decreased apoptosis of MSCs after OGD treatment but also promoted the secretion of IGF‐1 and HGF in MSCs. Treatment with culture supernatant of DSAP‐MSCs markedly reduced the percentage of apoptotic cardiomyocytes and increased the level of p‐Akt. Compared with the MSC group and SAP‐MSC group, DSAP‐MSC injection improved cardiac function and reduced infarct size, collagen content, and cell apoptosis. The number of Y chromosome–positive cells and microvessels in the DSAP‐MSC group was higher than those in the MSC group and SAP‐MSC group. Moreover, DSAP‐MSC transplantation down‐regulated the expression of IL‐6 and IL‐1β and up‐regulated the level of VEGF and HGF. Interestingly, miR‐21 was enriched in DSAP‐MSC‐derived exosomes (DSAP‐MSC‐Exos) and the protection against cardiomyocyte apoptosis by DSAP‐MSC‐Exos was inhibited when miR‐21 was knocked down. Furthermore, miR‐21 contributed to the improvement of cardiac function after DSAP‐MSC‐Exo injection in a rat model of MI. Additionally, the combination of DSAP and cardiotrophin‐1 (Ctf1) pretreatment further improved the survival of MSCs and the efficiency of MSC transplantation. We proposed QHREDGS‐modified SAP as an effective cell delivery system and demonstrated that MSC transplantation in this DSAP promoted angiogenesis and paracrine, thereby reducing scar size and cell apoptosis as well as improving cardiac function probably via exosome‐mediated miR‐21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuable way to improve the survival of MSCs and the efficiency of MSC transplantation after MI.—Cai, H., Wu, F.‐Y., Wang, Q.‐L., Xu, P., Mou, F.‐F., Shao, S.‐J., Luo, Z.‐R., Zhu, J., Xuan, S.‐S., Lu, R., Guo, H.‐D. Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction. FASEB J. 33, 8306–8320 (2019). www.fasebj.org