Jie Liu

BACKGROUND: Adult mammalian cardiomyocytes exhibit some capacity to reenter the cell cycle after ischemic injury. However, activated cardiomyocytes rapidly undergo cell cycle rearrest shortly after activation. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of cardiac regeneration; however, their involvement in the process of cell cycle rearrest remains unexplored. METHODS: Bulk RNA-sequencing was used to screen for lncRNAs differentially expressed during myocardial injury. Loss- and gain-of-function approaches were used to assess the role of lncRNA in cardiomyocyte proliferation and cardiac regeneration after myocardial infarction (MI). RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying regulatory mechanisms. RESULTS: We identified a cardiomyocyte-specific lncRNA downregulated after myocardial injury and named it cardiomyocyte-specific transcript promoting proliferation (CSTPP). CSTPP overexpression enhanced neonatal rat ventricular myocyte proliferation, whereas its knockdown exerted the opposite effects. In vivo, CSTPP deletion attenuated cardiomyocyte proliferation, leading to exacerbated cardiac dysfunction post-MI. Conversely, CSTPP overexpression promoted cardiomyocyte proliferation and improved cardiac function. Furthermore, CDKN1A (cyclin-dependent kinase inhibitor 1A) was found to be upregulated in cardiomyocytes localized at the border zone after MI, which was aggravated by CSTPP knockout and abrogated by CSTPP overexpression. Mechanistically, we showed that CSTPP interacts with YBX1 (Y box–binding protein 1), reinforcing the interaction between YBX1 and UPF1 (upstream frameshift 1), thereby enhancing UPF1 recruitment to CDKN1A mRNA and accelerating its decay. Notably, CSTPP was downregulated in heart samples from patients with MI. CSTPP overexpression decreased CDKN1A expression and facilitated proliferation in human induced pluripotent stem cell–derived cardiomyocytes. CONCLUSIONS: Our findings identified CSTPP as a cardiomyocyte-specific lncRNA that functions to extend the activation window of the cardiomyocyte cell cycle after MI by stabilizing the YBX1-UPF1 interaction and thus facilitating the UPF1-mediated decay of CDKN1A mRNA. These results establish CSTPP as a promising therapeutic target for cardiac regeneration after MI.

The morphology and dynamics of microtubules (MTs) are controlled by the posttranslational modification of tubulins and are critical for maintaining cardiac electrophysiological homeostasis. Recent studies have revealed that vasohibin (VASH) is a detyrosinating enzyme of tubulin, and the upregulation of VASH1 (the dominant VASH isoform in the heart) induces MT detyrosination and impaired cardiac function. It remains unknown whether VASH1 participates in the pathogenesis of ventricular arrhythmia, a lethal pathological change in cardiac hypertrophy. Here, we demonstrated that significantly increased expression of VASH1 and detyrosinated α-tubulin led to greater susceptibility of the heart to ventricular arrhythmia, as indicated by an increased number of caffeine and isoproterenol-stimulated premature ventricular complexes (PVCs) on electrocardiography in transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice versus Sham mice. Cardiac-specific VASH1 overexpression induced MT detyrosination and polymerization, increasing the number of stimulated PVCs in normal mice. Optical mapping of the hearts demonstrated that VASH1 overexpression slowed electrical conductance. A mechanistic study revealed that VASH1 upregulation increased the Ca ²⁺ spark frequency and post-pacing Ca ²⁺ -release events, disrupted the transverse tubule network, and altered the distribution of connexin-43 at gap junctions. In cultured cardiomyocytes, VASH1 overexpression similarly increased Ca ²⁺ spark generation, which was abolished by the coexpression of tubulin tyrosine ligase (TTL) but not by TTL-E331Q, a mutant that lacks TTL catalytic activity but maintains its depolymerization effect. Furthermore, ablation of VASH1 decreased the susceptibility of TAC mice to ventricular arrhythmia by reducing the expression of arrhythmogenic substrates. In this study, we identified VASH1 as a master regulator of arrhythmogenesis in cardiac hypertrophy, reinforcing this protein as a promising therapeutic target for preventing ventricular arrhythmia.

Vasohibins (VASHs), comprising VASH-1 and VASH-2, were initially identified as regulators of angiogenesis. Recent studies, however, have unveiled their novel role in fibrosis and microtubule detyrosination. The dysregulated expression of VASHs is associated with several pathological processes, such as angiogenesis dysfunction, microtubule detyrosination, and fibrosis, contributing to various diseases. These findings suggest the pleiotropic effects of VASHs in multiple organs and systems beyond angiogenesis. This review explores the molecular properties of VASHs and their emerging functions in tubulin carboxyl activity and microtubule detyrosination—key to brain and cardiac remodeling. We also discuss the potential therapeutic applications of their interference in diseases such as tumorigenesis, as well as renal-, reproductive-, and liver-related diseases.

The KCNE2 protein is encoded by the kcne2 gene and is a member of the KCNE protein family, also known as the MinK-related protein 1 (MiRP1). It is mostly present in the epicardium of the heart and gastric mucosa, and it is also found in the thyroid, pancreatic islets, liver and lung, among other locations, to a lesser extent. It is involved in numerous physiological processes because of its ubiquitous expression and partnering promiscuity, including the modulation of voltage-dependent potassium and calcium channels involved in cardiac action potential repolarization, and regulation of secretory processes in multiple epithelia, such as gastric acid secretion, thyroid hormone synthesis, generation and secretion of cerebrospinal fluid. Mutations in the KCNE2 gene or aberrant expression of the protein may play a critical role in cardiovascular, neurological, metabolic and multisystem disorders. This article provides an overview of the advancements made in understanding the physiological functions in organismal homeostasis and the pathophysiological consequences of KCNE2 in multisystem diseases.

Background: Vascular smooth muscle cell (VSMC) proliferation is involved in many types of arterial diseases, including neointima hyperplasia, in which Ca ²⁺ has been recognized as a key player. However, the physiological role of Ca ²⁺ release via inositol 1,4,5‐trisphosphate receptors (IP ₃ Rs) from endoplasmic reticulum in regulating VSMC proliferation has not been well determined. Methods and Results: Both in vitro cell culture models and in vivo mouse models were generated to investigate the role of IP ₃ Rs in regulating VSMC proliferation. Expression of all 3 IP ₃ R subtypes was increased in cultured VSMCs upon platelet‐derived growth factor‐BB and FBS stimulation as well as in the left carotid artery undergoing intimal thickening after vascular occlusion. Genetic ablation of all 3 IP ₃ R subtypes abolished endoplasmic reticulum Ca ²⁺ release in cultured VSMCs, significantly reduced cell proliferation induced by platelet‐derived growth factor‐BB and FBS stimulation, and also decreased cell migration of VSMCs. Furthermore, smooth muscle–specific deletion of all IP ₃ R subtypes in adult mice dramatically attenuated neointima formation induced by left carotid artery ligation, accompanied by significant decreases in cell proliferation and matrix metalloproteinase‐9 expression in injured vessels. Mechanistically, IP ₃ R‐mediated Ca ²⁺ release may activate cAMP response element–binding protein, a key player in controlling VSMC proliferation, via Ca ²⁺ /calmodulin‐dependent protein kinase II and Akt. Loss of IP ₃ Rs suppressed cAMP response element–binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca ²⁺ permeable ionophore, ionomycin, can reverse cAMP response element–binding protein phosphorylation in IP ₃ R triple knockout VSMCs. Conclusions: Our results demonstrated an essential role of IP ₃ R‐mediated Ca ²⁺ release from endoplasmic reticulum in regulating cAMP response element–binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.

Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H⁺-ATPase subunit V_od1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1^AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy.

Transforming growth factor-beta 2 (TGF-β2), an important member of the TGF-β family, is a secreted protein that is involved in many biological processes, such as cell growth, proliferation, migration, and differentiation. TGF-β2 had been thought to be functionally identical to TGF-β1; however, an increasing number of recent studies uncovered the distinctive features of TGF-β2 in terms of its expression, activation, and biological functions. Mice deficient in TGF-β2 showed remarkable developmental abnormalities in multiple organs, especially the cardiovascular system. Dysregulation of TGF-β2 signalling was associated with tumorigenesis, eye diseases, cardiovascular diseases, immune disorders, as well as motor system diseases. Here, we provide a comprehensive review of the research progress in TGF-β2 to support further research on TGF-β2.

K_V channel-interacting proteins (KChIP1-4) belong to a family of Ca²⁺-binding EF-hand proteins that are able to bind to the N-terminus of the K_V4 channel α-subunits. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the fast inactivating-K_V4 currents. As the auxiliary subunit, KChIPs are critically involved in regulating the surface protein expression and gating properties of K_V4 channels. Mechanistically, KChIP1, KChIP2, and KChIP3 promote the translocation of K_V4 channels to the cell membrane, accelerate voltage-dependent activation, and slow the recovery rate of inactivation, which increases K_V4 currents. By contrast, KChIP4 suppresses K_V4 trafficking and eliminates the fast inactivation of K_V4 currents. In the heart, I_Ks, I_Ca,L, and I_Na can also be regulated by KChIPs. I_Ca,L and I_Na are positively regulated by KChIP2, whereas I_Ks is negatively regulated by KChIP2. Interestingly, KChIP3 is also known as downstream regulatory element antagonist modulator (DREAM) because it can bind directly to the downstream regulatory element (DRE) on the promoters of target genes that are implicated in the regulation of pain, memory, endocrine, immune, and inflammatory reactions. In addition, all the KChIPs can act as transcription factors to repress the expression of genes involved in circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of several neurological and cardiovascular diseases. For example, KChIP2 is decreased in failing hearts, while loss of KChIP2 leads to increased susceptibility to arrhythmias. KChIP3 is increased in Alzheimer’s disease and amyotrophic lateral sclerosis, but decreased in epilepsy and Huntington’s disease. In the present review, we summarize the progress of recent studies regarding the structural properties, physiological functions, and pathological roles of KChIPs in both health and disease. We also summarize the small-molecule compounds that regulate the function of KChIPs. This review will provide an overview and update of the regulatory mechanism of the KChIP family and the progress of targeted drug research as a reference for researchers in related fields.

KV channel-interacting proteins (KChIPs) belong to a family of Ca2+-binding EF-hand proteins that are able to bind to the N-terminus of the KV4 channel α-subunits. As the auxiliary subunit, KChIPs are critically involved in regulating the amplitude and gating properties of KV4 channels by modulating their cell surface trafficking, voltage-dependent activation, inactivation kinetics, and recovery rate from inactivation. IKs, ICa,L, and INa can also be regulated by KChIPs. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the KV4 currents. Interestingly, all KChIPs can act as transcription factors to control the expression of genes involved in pain, memory, and circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of many diseases, such as arrhythmia, heart failure, Alzheimer's disease, etc. In this review, we summarize the research progress of KChIPs in their structural properties, physiological functions, and pathological roles in disease progression, and provide an overview of the therapeutic potential of KChIPs as pharmacological targets for associated disorders.