Role of natural products in cardiovascular disease.

As the world's aging population increases, cardiovascular diseases (CVDs) associated with aging deserve increasing attention. CVD in association with age is considered a major cause of morbidity and mortality worldwide. In this review, we provide an overview of the key molecular pathways, cellular processes such as autophagy, oxidative stress, inflammatory responses, myocardial remodeling and ischemia-refocused injury that accompany CVD as well as the natural products of targeting these mechanisms and some of the dietary habits that have been studied in cardiovascular-related diseases.

Status of Research on Sestrin2 and Prospects for its Application in Therapeutic Strategies Targeting Myocardial Aging.

Cardiac aging is accompanied by changes in the heart at the cellular and molecular levels, leading to alterations in cardiac structure and function. Given today's increasingly aging population, the decline in cardiac function caused by cardiac aging has a significant impact on quality of life. Antiaging therapies to slow the aging process and attenuate changes in cardiac structure and function have become an important research topic.

Sestrin2 is an endogenous antioxidant that improves contractile function in the heart during exposure to ischemia and reperfusion stress.

Sestrin2 (Sesn2) is a stress-inducible protein that plays a critical role in the response to ischemic stress. We recently recognized that Sesn2 may protect the heart against ischemic insults by reducing the generation of reactive oxygen species (ROS). After 45 min of ischemia followed by 24 h of reperfusion, myocardial infarcts were significantly larger in Sesn2 KO hearts than in wild-type hearts.

Sestrin 2, a potential star of antioxidant stress in cardiovascular diseases.

Physiological reactive oxygen species (ROS) play an important role in cellular signal transduction. However, excessive ROS is an important pathological mechanism in most cardiovascular diseases (CVDs), such as myocardial aging, cardiomyopathy, ischemia/reperfusion injury (e.g.

Substrate metabolism regulated by Sestrin2-mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart.

Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4-6 months), aged WT (24-26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4-6 months) underwent transverse aortic constriction (TAC) for pressure overload.

Sestrin 2 controls the cardiovascular aging process via an integrated network of signaling pathways.

As an inevitable biological process, cardiovascular aging is the greatest risk factor for cardiovascular diseases (CVDs). Sestrin 2 (Sesn2), a stress-inducible and age-related protein associated with various stress conditions, plays a pivotal role in slowing this process. It acts as an anti-aging agent, mainly through its antioxidant enzymatic activity and regulation of antioxidant signaling pathways, as well as by activating adenosine monophosphate-activated protein kinase and inhibiting mammalian target of rapamycin complex 1.

Sestrin2 modulates cardiac inflammatory response through maintaining redox homeostasis during ischemia and reperfusion.

Ischemia heart disease is the leading cause of death world-widely and has increased prevalence and exacerbated myocardial infarction with aging. Sestrin2, a stress-inducible protein, declines with aging in the heart and the rescue of Sestrin2 in the aged mouse heart improves the resistance to ischemic insults caused by ischemia and reperfusion. Here, through a combination of transcriptomic, physiological, histological, and biochemical strategies, we found that Sestrin2 deficiency shows an aged-like phenotype in the heart with excessive oxidative stress, provoked immune response, and defected myocardium structure under physiological condition.

The Emerging Role of Sestrin2 in Cell Metabolism, and Cardiovascular and Age-Related Diseases.

Sestrins (Sesns), including Sesn1, Sesn2, and Sesn3, are cysteine sulfinyl reductases that play critical roles in the regulation of peroxide signaling and oxidant defense. Sesn2 is thought to regulate cell growth, metabolism, and survival response to various stresses, and act as a positive regulator of autophagy. The anti-oxidative and anti-aging roles of Sesn2 have been the focus of many recent studies.

The value of plasma fibrillin-1 level in patients with spontaneous coronary artery dissection.

Background: Spontaneous coronary artery dissection (SCAD) has emerged as an important etiology of myocardial infarction and sudden death, especially in young women. Early diagnosis is essential for appropriate management.

Objectives: To explore the value of plasma fibrillin-1 (FBN1) levels in patients with SCAD.

Mitochondrial Complex I Inhibition by Metformin Limits Reperfusion Injury.

Transient, reversible blockade of complex I during early reperfusion after ischemia limits cardiac injury. We studied the cardioprotection of high dose of metformin in cultured cells and mouse hearts via the novel mechanism of acute downregulation of complex I. The effect of high dose of metformin on complex I activity was studied in isolated heart mitochondria and cultured H9c2 cells.

Dichloroacetate Ameliorates Cardiac Dysfunction Caused by Ischemic Insults Through AMPK Signal Pathway-Not Only Shifts Metabolism.

Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), regulates substrate metabolism in the heart. AMP-activated protein kinase (AMPK) is an age-related energy sensor that protects the heart from ischemic injury. This study aims to investigate whether DCA can protect the heart from ischemic injury through the AMPK signaling pathway.

Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility.

Clinical observations have demonstrated a link between chronic pain and increased ischemic heart disease mortality, but the mechanisms remain elusive. Reactive aldehydes have recently been confirmed as a new player in pain pathologies, while our previous study demonstrated that reactive aldehydes (4-HNE) induced carbonyl stress contributing to myocardial ischemic intolerance. The aim of this study was to explore whether chronic pain increases susceptibility to myocardial ischemia/reperfusion (MI/R) injury and to investigate the underlying mechanisms focusing on toxic aldehyde and carbonyl stress.

Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury.

Aims: A longevity gene, Sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress, and exercise. The objective of this study is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults.

Methods And Results: Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models.

Sestrin2 prevents age-related intolerance to post myocardial infarction via AMPK/PGC-1α pathway.

We have revealed that a novel stress-inducible protein, Sestrin2, declines in the heart with aging. Moreover, there is an interaction between Sestrin2 and energy sensor AMPK in the heart in response to ischemic stress. The objective of this study is to determine whether Sestrin2-AMPK complex modulates PGC-1α in the heart and protects the heart from ischemic insults.

Activated protein C protects against pressure overload-induced hypertrophy through AMPK signaling.

We found that the anticoagulant plasma protease, activated protein C (APC), stimulates the energy sensor kinase, AMPK, in the stressed heart by activating protease-activated receptor 1 (PAR1) on cardiomyocytes. Wild-type (WT) and AMPK-kinase dead (KD) transgenic mice were subjected to transverse aortic constriction (TAC) surgery. The results demonstrated that while no phenotypic differences can be observed between WT and AMPK-KD mice under normal physiological conditions, AMPK-KD mice exhibit significantly larger hearts after 4 weeks of TAC surgery.

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy.

AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction.

Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism.

A novel stress-inducible protein, Sestrin2 (Sesn2), declines in the heart with aging. AMPK has emerged as a pertinent stress-activated kinase that has been shown to have cardioprotective capabilities against myocardial ischemic injury. We identified the interaction between Sesn2 and AMPK in the ischemic heart.

Cardioprotective actions of Notch1 against myocardial infarction via LKB1-dependent AMPK signaling pathway.

AMP-activated protein kinase (AMPK) signaling pathway plays a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. Notch1 signaling in the adult myocardium is also activated in response to ischemic stress. However, the relationship between Notch1 and AMPK signaling pathways during ischemia remains unclear.

The protective effect of trimetazidine on myocardial ischemia/reperfusion injury through activating AMPK and ERK signaling pathway.

Introduction: Trimetazidine (TMZ) is an anti-anginal drug that has been widely used in Europe and Asia. The TMZ can optimize energy metabolism via inhibition of long-chain 3-ketoacyl CoA thiolase (3-KAT) in the heart, with subsequent decrease in fatty acid oxidation and stimulation of glucose oxidation. However, the mechanism by which TMZ aids in cardioprotection against ischemic injury has not been characterized.

Cardiac-Specific Deletion of the Pdha1 Gene Sensitizes Heart to Toxicological Actions of Ischemic Stress.

Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. We generated inducible cardiac-specific PDH E1α knockout (CreER(T2)-PDH(flox/flox)) mice that demonstrated a high mortality rate. It was hypothesized that PDH modulating cardiac glucose metabolism is crucial for heart functions under normal physiological and/or stress conditions.

The Modulation of Cardiac Contractile Function by the Pharmacological and Toxicological Effects of Urocortin2.

Urocortin2 (Ucn2) has been revealed to enhance cardiac function in heart failure. However, the pharmacological and toxicological effects of Ucn2 on cardiomyocytes are incompletely understood. In this study, we investigated the possible mechanisms of Ucn2 on mediating the contractility of cardiomyocytes.

In vivo oxidation, platelet activation and simultaneous occurrence of natural immunity in atherosclerosis-prone mice.

Background: Several murine models are susceptible to atherosclerosis, such as low density-lipoprotein receptor-deficient (LDLR-/-) and apolipoprotein E-deficient (apoE-/-) mice, and are used for studying pathophysiological mechanisms. Atherosclerotic lesions in the aortic valve and thoracic/abdominal aorta are commonly associated with hyperlipidemia. We recently demonstrated the development of large atherosclerotic plaques in Helicobacter pylori-infected heterozygous LDLR+/- apoE+/- mice.

Autoimmunity, infectious immunity, and atherosclerosis.

Introduction: Vascular inflammation is common in certain systemic autoimmune diseases and contributes to the oxidation of low-density lipoprotein (oxLDL) and oxLDL/beta2-glycoprotein I (beta2GPI) complex formation. These complexes have been implicated as proatherogenic autoantigens that participate in the development of atherosclerotic disease.

Discussion: We have demonstrated that the in vitro macrophage uptake of oxLDL/beta2GPI complexes increases in the presence of IgG anti-beta2GPI antibodies and that IgG immune complexes containing oxLDL/beta2GPI upregulate the expression of both scavenger and Fcgamma receptors to activate beta2GPI specific T cells.