Current Vascular Pharmacology - Volume 13, Issue 4, 2015

In Chinese medicine, Zheng-hou, instead of disease, is used to define complex medical problems in clinical practice. In the postgenomics era, it becomes particularly compelling to review the application of Zheng-hou in characterizing complex clinical problems independent of disease or syndrome. While disease or syndrome describes a pathological phenotype or phenotypes, Zheng-hou spells the pathological phenome. Clinical Zheng-hou pharmacology (CZP) is an emerging clinical discipline that aims to leverage breakthroughs in the genome-wide solutions for complex medical problems through a combination of the current “omics” technology and the knowledge of Chinese medicine. The concept of CZP suggests that systematic and standard studies of multiple phenotypes will be important because of the collaborative cross between diversified external and internal factors at different levels both in vitro and in vivo. In this paper, we discuss the novel phenomic approaches to the understanding of Zheng-hou and the link of pharmacogenomics to personalized medicine through CZP, or pharmacophenomics. CZP enables ever-finer mapping of Zheng-hou and detection of dynamic variations in most current omics platforms. Although major challenges still remain in identifying and effectively investigating the diversity of Zheng-hou, CZP is expected to pave new paths to the systemic understanding of medical problems. While still at early stages in the clinical phenome domain, there remains great promise that CZP can help us realize the application of personalized medicine and contribute to rational holistic diagnosis and treatment.

Vascular diseases are usually caused by multifactorial pathogeneses involving genetic and environmental factors. Our current understanding of vascular disease is, however, based on the focused genotype/phenotype studies driven by the “one-gene/one-phenotype” hypothesis. Drugs with “pure target” at individual molecules involved in the pathophysiological pathways are the mainstream of current clinical treatments and the basis of combination therapy of vascular diseases. Recently, the combination of genomics, proteomics, and metabolomics has unraveled the etiology and pathophysiology of vascular disease in a big-data fashion and also revealed unmatched relationships between the omic variability and the much narrower definition of various clinical phenotypes of vascular disease in individual patients. Here, we introduce the phenomics strategy that will change the conventional focused phenotype/genotype/genome study to a new systematic phenome/genome/proteome approach to the understanding of pathophysiology and combination therapy of vascular disease. A phenome is the sum total of an organism’s phenotypic traits that signify the expression of genome and specific environmental influence. Phenomics is the study of phenome to quantitatively correlate complex traits to variability not only in genome, but also in transcriptome, proteome, metabolome, interactome, and environmental factors by exploring the systems biology that links the genomic and phenomic spaces. The application of phenomics and the phenome-wide associated study (PheWAS) will not only identify a systemically-integrated set of biomarkers for diagnosis and prognosis of vascular disease but also provide novel treatment targets for combination therapy and thus make a revolutionary paradigm shift in the clinical treatment of these devastating diseases.

Stroke is a leading cause of morbidity and mortality worldwide. It has been generally accepted that cerebrovascular remodeling during hypertension is one of the major contributors to the increased risk of stroke. Volume-regulated Cl- channel (VRCC) and calcium-activated Cl- channel (CaCC) are the two predominant types of Cl- channels in cerebral vascular smooth muscle cells (VSMC). Recent studies have demonstrated that ClC-3, a member of the voltage-gated ClC Cl- channel family, is the molecular candidate for VRCC in VSMC. And TMEM16A, a member of anoctamin family, is responsible for the native CaCC of VSMC in brain vessels. It has been shown that VRCC activity is enhanced but CaCC activity is decreased in cerebral VSMC, paralleling the severity of cerebrovascular remodeling induced by hypertension. In the present review, we will highlight the recent findings regarding the important roles of these two channels in VSMC proliferation, apoptosis, cell cycle regulation, vascular inflammation, reactive oxygen species production and cerebrovascular remodeling during the development of hypertension. In addition, the relationship between VRCC and clinical used agents for stroke prevention, such as statins, will be discussed. These findings suggest that Cl- channels may be potential new targets for the prevention of stroke.

Vascular disease constitutes the leading health problem throughout the entire world. Current therapies for vascular disease mainly rely on comprehensive strategies including control of risk factors, vascular interventions and conventional supportive treatments. To improve the preventive and therapeutic efficacies of current approaches, novel combinational therapies are required. Microparticles (MPs) are small membrane vesicles derived from cells undergoing stress, activation or apoptosis. They carry the characteristics of their parent cells, enabling them to serve as potential biomarkers for various diseases. Of note, MPs also have been shown to mediate cell communications through transferring membrane proteins, phospholipids and RNAs from their parent cells to recipient cells. Recent novel approaches have started to reveal the functions of MPs. In this review, we summarize the general concepts and the latest research progress in MPs. And the potential of MPs as novel targets of combinational therapy for vascular disease will be discussed.

Adrenomedullin is a highly conserved vasoactive peptide participating in a variety of physiological and pathophysiological processes including pregnancy, embryonic development, tumor progression and regulation of vascular tone. In particular, adrenomedullin expression is widely distributed throughout the cardiovascular system including heart, lungs, blood vessels and kidneys. The observation that adrenomedullin co-localizes with its receptors suggests that the peptide may act as an autocrine and/or paracrine factor in the regulation of cardiovascular function. In this review, we described the pathophysiological changes in plasma and local adrenomedullin associated with vascular endothelial function and the signaling mechanisms involved. Recent evidence has depicted a unique role of adrenomedullin in the regulation of vascular endothelial function in part through regulation of cAMP, cGMP and intracellular Ca²⁺ mobilization. This review summarized vascular endothelial actions of adrenomedullin under both physiological and pathophysiological conditions in an effort to provide guidance for the clinical application of adrenomedullin in vascular diseases.

Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.

Background and Objectives: Stroke is a disease with high morbidity, disability, and fatality. Since ischemic stroke is the most common kind of stroke, increasing attention has been paid to its prevention and treatment. Given the limitations of conventional medicine, there is growing interest in Chinese Medicine (CM), especially Chinese Patent Medicine (CPM) for its convenience and stability. Studies of CM show that Chinese Patent Medicines for Tonifying Qi and Promoting Blood Circulation (CPMs-TQPBC) are one of the most common and effective categories of all clinical CPMs in China. Methods: This review investigated and summarized the randomized controlled trials (RCT) of CPMs-TQPBC combined with conventional interventions in the last 10 years. Results: Trial results demonstrated the potential in reducing the endpoints and improving neurologic impairments, body movements, Barthel index, quality of life, and certain biomarkers. Furthermore, certain CM syndromes were alleviated with rare adverse events. Advantages of interventions combined with CPMs-TQPBC for patients with cerebral infarction were discovered. Compared with the Chinese patent medicines for promoting blood circulation (CPMs-PBC) alone, CPMs for both tonifying qi and promoting blood circulation exhibited noticeably better effects. The underlying reasons could be related to the improvement of microcirculation in the brain, protection against ischemic reperfusion injury, generation of neuroprotective factors, and inhibition of apoptosis. Conclusion: Under the circumstances of qi deficiency and blood stasis syndrome (QDBSS) (Qixu-Xueyu Zheng), CPMs- TQPBC showed a substantial difference. More trials focusing on specific patient groups should be carried out to corroborate and expand the findings.

Objective: To reveal the cutoff point and influencing factors in the dynamic change in phenotypic group in patients with stable angina pectoris (SAP) after Xinxuekang capsule treatment. Methods: Five hundred and seventy-six SAP patients were randomly assigned to receive Xinxuekang (XXK) capsules or Compound Danshen (CDS) tablets for 8 weeks. Global similarity degree analysis and nonlinear mixed effects modeling (NONMEM) were employed to reveal the cutoff points and influencing factors in dynamic changes in the SAP phenotypic group. The phenotypic group was defined as the six phenotypes in SAP, including angina, choking sensation in the chest, palpitations, dark purple lips, ecchymosis on the tongue, and fine-choppy pulse, which were quantitatively evaluated on Days 0, 14, 28, 42, and 56. Results: Variation in the six individual phenotypes and distribution of the SAP phenotypic profile were similar between the two experimental groups, but cutoff points for changes in the SAP phenotypic group were 7.28 and 10.73 weeks in XXK and CDS groups, respectively. Degree of severity of SAP as well as study site significantly affected the tendency for change in the SAP Xueyu Zheng in both XXK and CDS treatment groups. Different Chinese patent drugs affected the tendency for change in phenotypic group in patients with SAP. XXK was superior to CDS in controlling a clinical phenotypic group. Conclusion: Based on global similarity degree analysis and NONMEM, the cutoff point and influencing factors in phenomic variation of SAP may be determined, to improve the development and modification of treatment regimens.

Objective: There are more than 300 million patients with hypertension in China, and at least 1 in 5 is using or has ever used Chinese Medicine (CM) treatment. Scope: This article reviews the efficacy and safety of CM as monotherapy and in combination with western medicine (WM) to explore its potential role in the clinical management of hypertension. Methods: Relevant articles were identified through PubMed, Chinese National Knowledge Infrastructure (CNKI) Database, VIP Chinese Journal Database, Wanfang Database, and China Biological Medicine Database (CBM-disc) search (up to 31 March, 2013). Findings: A total of 27 RCTs and 7 systematic reviews (including meta-analyses) were identified. These articles suggested that although as monotherapy, CM has limited effect for hypertension, while combined with WM, it does have a favorable effect of antihypertension. The combination therapy could not only improve the quality of life and the symptoms of hypertensive patients, such as dizziness and headache, but also stabilize blood pressure variability (BP). Moreover, the combined treatment of CM and WM may further reduce BP to the target levels for patients failed with hypertension control. Besides, the combination therapy also has more favorable effects than any WM monotherapy in protecting target organs as well as avoiding adverse reactions. Conclusion: When combined with WM, CM as a complementary treatment approach has certain effects for the control of hypertension and protection of target organs. However, more well-designed studies should be conducted to make a solid conclusion.

Background: Increasing attention is being given to the use of Chinese medicine (CM) for preventing and healing vascular complications of chronic ulcerative lesions of diabetic foot. Objectives: The purposes of this paper are to describe some benefits of CM for the treatment of diabetic foot and to provide some expert opinions based on some case studies and evidence from documented Chinese traditional medicine literature. Methods: A critical review of the literature and a case report. Results: Cumulative evidence in the literature indicate that CM preparations possess anti-inflammatory activities, antioxygenation, antibiosis, antibacterial, antiallergic and beneficial effect on the viability of fibroblasts. Case record suggested that after CM treatment the patient with Wagner Grade IV ulcers healed completely. Conclusion: It is becoming increasingly important for integrated CM and biomedicine therapy to treat diabetes-related vascular complications. The opportunities for effective CM interventions are significant, and more solid evidence is warranted to show the efficacy of CM in the treatment of diabetic foot ulcers in the near future.

Background: The clinical benefits of the application of renin-angiotensin system (RAS) blockade, i.e., angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), have been well established in patients with diabetic nephropathies (DN). Since the combination therapy with Chinese Medicine (CM) and conventional western medicine (CWM) is considered an effective approach to many conditions, many CM experts have investigated the combination therapy with CM and RAS blockade to look for new approaches to DN. Aim: The purpose of this article is to review the antiproteinuric and renopretective effects of combination therapy of CM and ACEI/ARBs for the management of DN. Methods: Relevant articles were identified through PubMed and three major Chinese databases (CBM, CAJD, CSTJ) up to March 2013. Findings: The results of the current literature are consistent with CM theories (e.g., tonifying and replenishing CM with blood-activating and stasis-resolving CM as major therapeutic strategies for the management of DN). 91 clinical articles on the combination therapy of CM and ACEI/ARBs were identified, but only eight randomized controlled trials were eventually included in the present review. The results were not always consistent: three articles reported that CM conferred both anti-proteinuric and reno-protective effects in addition to ACEI/ARBs; three articles reported that CM failed to provide additional reno-protective benefits; two articles reported that CM conferred neither anti-proteinuric nor renoprotective effects in addition to ACEI/ARBs. Conclusion: Current literature indicates that combination therapy with CM and ACEI/ARBs might have polypharmacological anti-proteinuric and reno-protective effects for the management of DN. Shortcomings concerning the interaction between CM and CWM, methodology, and study design need to be addressed in future research.

Coronary heart disease (CHD) is one of the leading causes of death worldwide. Moreover, angina pectoris is one of the most important types of CHD. Therefore, prevention and effective treatment of angina pectoris is of utmost importance in both China and western countries. However, undesirable effects of antianginal therapy do influence treatment adherence to a certain extent. Therefore, it’s not surprising that, complementary and alternative medicine (CAM), including Chinese medicine (CM), are widely welcomed among patients with CHD, hoping that it might complement western medicine. In our previous studies, blood stasis syndrome (BSS) (Xueyu Zheng) was the main syndrome (Zheng-hou) of angina pectoris. Currently, China Food and Drug Administration authoritatively recommended more than 200 Chinese patent medicines (CPMs) as complementary or adjunctive therapies for symptom management and enhancing quality of life along with mainstream care on angina pectoris management in mainland China. This paper reviewed 4 kinds of most frequently-used CPMs by promoting blood circulation and removing blood stasis in the treatment of angina pectoris. It aims to evaluate the current evidence of CPMs in combination therapy for angina pectoris. This review indicated that CPMs as adjunctive treatment to routine antianginal therapy play an active role in reducing the incidence of primary endpoint events, decreasing anginal attack rate, and improving electrocardiogram. Additionally, CPMs have been proven relatively safe. Further rigorously designed clinical trials should be conducted to confirm the results.

Background: Combination treatment has been a popular therapeutic strategy in diabetes and related vascular complications. However, the reasonable dosing regimen in combination treatment remains unknown. Nowadays, pharmacokinetics (PK) is becoming a useful approach to reveal the mechanisms of drug-drug interactions (DDIs) and reasonable drug compatibility in combination treatment. Scope: This article reviews the pharmacokinetics studies on combination therapies for diabetes and its vascular complications to reveal the mechanisms of reasonable drug compatibility for optimizing drug combination treatment. Methods: Relevant articles were identified through the PubMed search (from January 2006 to December 2012) in English and the CNKI and Wan Wei websites in Chinese (from January 2000 to December 2012). Findings: Thirty-six articles were identified, including 15 on DDIs, 8 on pharmacological mechanism or metabolic pathways, and 6 on non-drug factors. DDIs studies showed the changes of drug-effect in combination treatment, which could guide physicians to administer anti-hyperglycemic agent in best time and in optimal order. PK studies based on pharmacological mechanism or metabolic pathways revealed reasonable compatibility of fixed-dose combination (FDC). A combination of pharmacokinetics/pharmacodynamics (PK/PD) and population pharmacokinetics (PopPK) and the development of PK/PD models in PK studies were good ways to determine the rational use and treatment effects in combined therapies. There were other 7 PK studies on the compatibility of preparations in Chinese medicine, which also outlined the features of DDIs in herbal drugs. Conclusion: PK studies may be useful to resolve the growing and complex issue of drug combinations to devise reasonable treatment regimens and to make physicians recognize the mechanisms of combined therapies. However, more longterm, comprehensive PK studies on combination therapy should be conducted in future.