Cardiovascular disease(CVD)remains one of the leading causes of mortality among adults globally,with continuously rising morbidity and mortality rates.Metabolic disorders are closely linked to various cardiovascular d...Cardiovascular disease(CVD)remains one of the leading causes of mortality among adults globally,with continuously rising morbidity and mortality rates.Metabolic disorders are closely linked to various cardiovascular diseases and play a critical role in their pathogenesis and progression,involving multifaceted mechanisms such as altered substrate utilization,mitochondrial structural and functional dysfunction,and impaired ATP synthesis and transport.In recent years,the potential role of peroxisome proliferator-activated receptors(PPARs)in cardiovascular diseases has garnered significant attention,particularly peroxisome proliferator-activated receptor alpha(PPARα),which is recognized as a highly promising therapeutic target for CVD.PPARαregulates cardiovascular physiological and pathological processes through fatty acid metabolism.As a ligand-activated receptor within the nuclear hormone receptor family,PPARαis highly expressed in multiple organs,including skeletal muscle,liver,intestine,kidney,and heart,where it governs the metabolism of diverse substrates.Functioning as a key transcription factor in maintaining metabolic homeostasis and catalyzing or regulating biochemical reactions,PPARαexerts its cardioprotective effects through multiple pathways:modulating lipid metabolism,participating in cardiac energy metabolism,enhancing insulin sensitivity,suppressing inflammatory responses,improving vascular endothelial function,and inhibiting smooth muscle cell proliferation and migration.These mechanisms collectively reduce the risk of cardiovascular disease development.Thus,PPARαplays a pivotal role in various pathological processes via mechanisms such as lipid metabolism regulation,anti-inflammatory actions,and anti-apoptotic effects.PPARαis activated by binding to natural or synthetic lipophilic ligands,including endogenous fatty acids and their derivatives(e.g.,linoleic acid,oleic acid,and arachidonic acid)as well as synthetic peroxisome proliferators.Upon ligand binding,PPARαactivates the nuclear receptor retinoid X receptor(RXR),forming a PPARα-RXR heterodimer.This heterodimer,in conjunction with coactivators,undergoes further activation and subsequently binds to peroxisome proliferator response elements(PPREs),thereby regulating the transcription of target genes critical for lipid and glucose homeostasis.Key genes include fatty acid translocase(FAT/CD36),diacylglycerol acyltransferase(DGAT),carnitine palmitoyltransferase I(CPT1),and glucose transporter(GLUT),which are primarily involved in fatty acid uptake,storage,oxidation,and glucose utilization processes.Advancing research on PPARαas a therapeutic target for cardiovascular diseases has underscored its growing clinical significance.Currently,PPARαactivators/agonists,such as fibrates(e.g.,fenofibrate and bezafibrate)and thiazolidinediones,have been extensively studied in clinical trials for CVD prevention.Traditional PPARαagonists,including fenofibrate and bezafibrate,are widely used in clinical practice to treat hypertriglyceridemia and low high-density lipoprotein cholesterol(HDL-C)levels.These fibrates enhance fatty acid metabolism in the liver and skeletal muscle by activating PPARα,and their cardioprotective effects have been validated in numerous clinical studies.Recent research highlights that fibrates improve insulin resistance,regulate lipid metabolism,correct energy metabolism imbalances,and inhibit the proliferation and migration of vascular smooth muscle and endothelial cells,thereby ameliorating pathological remodeling of the cardiovascular system and reducing blood pressure.Given the substantial attention to PPARα-targeted interventions in both basic research and clinical applications,activating PPARαmay serve as a key therapeutic strategy for managing cardiovascular conditions such as myocardial hypertrophy,atherosclerosis,ischemic cardiomyopathy,myocardial infarction,diabetic cardiomyopathy,and heart failure.This review comprehensively examines the regulatory roles of PPARαin cardiovascular diseases and evaluates its clinical application value,aiming to provide a theoretical foundation for further development and utilization of PPARα-related therapies in CVD treatment.展开更多
文摘Cardiovascular disease(CVD)remains one of the leading causes of mortality among adults globally,with continuously rising morbidity and mortality rates.Metabolic disorders are closely linked to various cardiovascular diseases and play a critical role in their pathogenesis and progression,involving multifaceted mechanisms such as altered substrate utilization,mitochondrial structural and functional dysfunction,and impaired ATP synthesis and transport.In recent years,the potential role of peroxisome proliferator-activated receptors(PPARs)in cardiovascular diseases has garnered significant attention,particularly peroxisome proliferator-activated receptor alpha(PPARα),which is recognized as a highly promising therapeutic target for CVD.PPARαregulates cardiovascular physiological and pathological processes through fatty acid metabolism.As a ligand-activated receptor within the nuclear hormone receptor family,PPARαis highly expressed in multiple organs,including skeletal muscle,liver,intestine,kidney,and heart,where it governs the metabolism of diverse substrates.Functioning as a key transcription factor in maintaining metabolic homeostasis and catalyzing or regulating biochemical reactions,PPARαexerts its cardioprotective effects through multiple pathways:modulating lipid metabolism,participating in cardiac energy metabolism,enhancing insulin sensitivity,suppressing inflammatory responses,improving vascular endothelial function,and inhibiting smooth muscle cell proliferation and migration.These mechanisms collectively reduce the risk of cardiovascular disease development.Thus,PPARαplays a pivotal role in various pathological processes via mechanisms such as lipid metabolism regulation,anti-inflammatory actions,and anti-apoptotic effects.PPARαis activated by binding to natural or synthetic lipophilic ligands,including endogenous fatty acids and their derivatives(e.g.,linoleic acid,oleic acid,and arachidonic acid)as well as synthetic peroxisome proliferators.Upon ligand binding,PPARαactivates the nuclear receptor retinoid X receptor(RXR),forming a PPARα-RXR heterodimer.This heterodimer,in conjunction with coactivators,undergoes further activation and subsequently binds to peroxisome proliferator response elements(PPREs),thereby regulating the transcription of target genes critical for lipid and glucose homeostasis.Key genes include fatty acid translocase(FAT/CD36),diacylglycerol acyltransferase(DGAT),carnitine palmitoyltransferase I(CPT1),and glucose transporter(GLUT),which are primarily involved in fatty acid uptake,storage,oxidation,and glucose utilization processes.Advancing research on PPARαas a therapeutic target for cardiovascular diseases has underscored its growing clinical significance.Currently,PPARαactivators/agonists,such as fibrates(e.g.,fenofibrate and bezafibrate)and thiazolidinediones,have been extensively studied in clinical trials for CVD prevention.Traditional PPARαagonists,including fenofibrate and bezafibrate,are widely used in clinical practice to treat hypertriglyceridemia and low high-density lipoprotein cholesterol(HDL-C)levels.These fibrates enhance fatty acid metabolism in the liver and skeletal muscle by activating PPARα,and their cardioprotective effects have been validated in numerous clinical studies.Recent research highlights that fibrates improve insulin resistance,regulate lipid metabolism,correct energy metabolism imbalances,and inhibit the proliferation and migration of vascular smooth muscle and endothelial cells,thereby ameliorating pathological remodeling of the cardiovascular system and reducing blood pressure.Given the substantial attention to PPARα-targeted interventions in both basic research and clinical applications,activating PPARαmay serve as a key therapeutic strategy for managing cardiovascular conditions such as myocardial hypertrophy,atherosclerosis,ischemic cardiomyopathy,myocardial infarction,diabetic cardiomyopathy,and heart failure.This review comprehensively examines the regulatory roles of PPARαin cardiovascular diseases and evaluates its clinical application value,aiming to provide a theoretical foundation for further development and utilization of PPARα-related therapies in CVD treatment.
