The Role of FGF21 in the Pathogenesis of Cardiovascular Disease

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The Role of FGF21 in the Pathogenesis of Cardiovascular Disease

Fibroblast growth factor 21 (FGF21), a metabolic regulator with pleiotropic effects on glucose and lipid metabolism, has emerged as a critical mediator in cardiovascular health. As cardiovascular diseases (CVDs) remain the leading cause of global morbidity and mortality, understanding the molecular mechanisms by which FGF21 influences cardiovascular pathophysiology offers promising therapeutic insights. This article comprehensively examines the role of FGF21 in key CVDs, including coronary heart disease (CHD), myocardial infarction (MI), cardiomyopathy (CMP), and heart failure (HF), while dissecting its protective mechanisms across cellular and systemic levels.

FGF21 and Coronary Heart Disease

Coronary heart disease, primarily driven by atherosclerosis, involves lipid deposition, endothelial dysfunction, and plaque formation in coronary arteries. Clinical and preclinical studies highlight FGF21 as a biomarker and therapeutic agent in CHD. In patients with unstable angina pectoris (UAP), serum FGF21 levels are significantly elevated compared to stable angina or healthy controls, suggesting its role as a predictor of acute coronary events. Paradoxically, a U-shaped relationship exists between serum FGF21 levels and mortality in CHD patients, where both low and high concentrations correlate with increased cardiovascular risk.

Mechanistically, FGF21 alleviates atherosclerosis through multiple pathways:

  1. Endothelial Protection: FGF21 prevents endothelial dysfunction by activating the calcium/calmodulin-dependent kinase kinase 2 (CaMKK2)-AMP-activated protein kinase (AMPK) pathway, enhancing endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide production. This reduces oxidative stress and apoptosis in endothelial cells exposed to hyperglycemia or oxidized low-density lipoprotein (ox-LDL).
  2. Lipid Metabolism Regulation: In apolipoprotein E-deficient (ApoE⁻/⁻) mice, FGF21 lowers serum triglycerides, total cholesterol, and LDL-C while raising HDL-C. It suppresses hepatic sterol regulatory element-binding protein-2 (SREBP-2), reducing cholesterol synthesis, and promotes ATP-binding cassette transporters ABCA1 and ABCG1 in macrophages to enhance cholesterol efflux.
  3. Anti-Inflammatory Effects: FGF21 inhibits the NLRP3 inflammasome, reducing interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) secretion. It also downregulates nuclear factor-κB (NF-κB) signaling, attenuating vascular inflammation and macrophage infiltration in atherosclerotic plaques.

FGF21 in Myocardial Infarction and Ischemia-Reperfusion Injury

Myocardial infarction, characterized by ischemia-induced cardiomyocyte death, triggers compensatory increases in cardiac and circulating FGF21. Serum FGF21 peaks within 24 hours post-MI and remains elevated for seven days, correlating with adverse outcomes like re-infarction and mortality. In rodent models, FGF21 deficiency exacerbates post-MI cardiac dysfunction, while exogenous FGF21 administration improves left ventricular ejection fraction and reduces infarct size.

Key cardioprotective mechanisms include:

  1. AMPK-SIRT1-PGC-1α Pathway Activation: FGF21 enhances mitochondrial biogenesis and energy metabolism via peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitigating ischemia-induced metabolic stress.
  2. Anti-Apoptotic Effects: FGF21 suppresses caspase-3 activity and Bax/Bcl-2 ratio in cardiomyocytes, reducing apoptosis. This is mediated through PI3K/Akt signaling and inhibition of Fas/FADD pathways.
  3. Adiponectin Induction: Muscle-derived FGF21 elevates plasma adiponectin, which promotes angiogenesis in the infarct border zone and reduces inflammatory cytokines like IL-6.

In ischemia-reperfusion (I/R) injury, FGF21 enhances autophagic flux via Beclin-1/vacuolar protein sorting 34 (Vps34), improving cell survival. It also attenuates oxidative stress by activating the Akt/glycogen synthase kinase 3β (GSK3β) pathway, preserving mitochondrial function.

FGF21 in Diabetic and Other Cardiomyopathies

Diabetic cardiomyopathy (DCM), marked by lipid accumulation and fibrosis, is modulated by FGF21 through:

  1. Lipotoxicity Mitigation: FGF21 suppresses CD36 and fatty acid transport protein (FATP) expression, reducing lipid uptake in cardiomyocytes. It activates AMPK/ACC/carnitine palmitoyltransferase I (CPT1), enhancing fatty acid oxidation and decreasing intracellular lipid droplets.
  2. Oxidative Stress Reduction: By upregulating superoxide dismutase 2 (SOD2) and uncoupling protein 3 (UCP3), FGF21 scavenges reactive oxygen species (ROS). The Nrf2/ARE pathway further bolishes antioxidant defenses.
  3. Anti-Fibrotic Actions: FGF21 inhibits transforming growth factor-β (TGF-β) signaling, reducing collagen deposition and cardiac fibrosis.

In hypertensive cardiomyopathy, FGF21 counteracts angiotensin II (Ang II)-induced hypertrophy by activating angiotensin-converting enzyme 2 (ACE2), which converts Ang II to Ang-(1–7). For alcoholic cardiomyopathy, FGF21 protects against mitochondrial dysfunction and oxidative stress, as evidenced by elevated cardiac FGF21 levels in chronic alcohol consumers.

FGF21 and Heart Failure

Heart failure, particularly with preserved ejection fraction (HFpEF), is associated with elevated circulating FGF21. In a cohort of 1,132 diabetic patients, lower baseline FGF21 predicted reduced major adverse cardiovascular events. Mechanisms include:

  1. SIRT1/PGC-1α Activation: Sodium-glucose cotransporter 2 (SGLT2) inhibitors upregulate FGF21, enhancing mitochondrial function and autophagy in cardiomyocytes.
  2. Inflammation Modulation: FGF21 reduces NLRP3 inflammasome activity and IL-1β release, attenuating maladaptive ventricular remodeling.

In cardiac cachexia, a complication of HF with reduced ejection fraction (HFrEF), elevated FGF21 correlates with muscle wasting, suggesting its role in metabolic dysregulation.

Challenges and Future Directions

Despite its therapeutic potential, FGF21 faces translational challenges. Its short half-life and instability necessitate engineered analogs like PF-05231023, which showed lipid-lowering effects in primates and diabetic patients. Concerns about bone loss in rodent models require further validation in humans. Moreover, the dual role of FGF21 as both a protective hormone and a marker of metabolic stress complicates its clinical interpretation.

Emerging strategies include combining FGF21 with glucagon-like peptide-1 (GLP-1) agonists to synergize metabolic benefits. Future studies must clarify tissue-specific FGF21 signaling and resolve discrepancies between preclinical and clinical observations.

10.1097/CM9.0000000000001890

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