Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Medicine

Background:

• Cardiac failure is a leading cause of death in pulmonary arterial hypertension (PH).
• Resistin-like molecules are implicated in PH pulmonary vascular remodeling.
• The direct role of resistin in PH-associated cardiac dysfunction remains unclear.

Purpose of the Study:

• To investigate the direct role of human resistin (Hresistin) in cardiac dysfunction and remodeling in PH.
• To explore the underlying mechanisms of Hresistin-induced cardiac pathology.
• To evaluate the therapeutic potential of targeting Hresistin in PH models.

Main Methods:

• Detection of Hresistin in human and rodent cardiac tissues.
• Generation of a cardiac-specific Hresistin-overexpressing humanized mouse model.
• Assessment of cardiac function, intracellular calcium handling, and molecular signaling pathways.
• Evaluation of an anti-Hresistin antibody in rodent PH models.

Main Results:

• Hresistin protein was detected in PH patient right ventricular (RV) tissue.
• Cardiac Hresistin overexpression induced RV dysfunction, dilated hearts, reduced contractility, and impaired calcium transients.
• Hresistin suppressed protein kinase A and AMP-activated protein kinase signaling.
• Hresistin triggered inflammation via high-mobility group box 1 signaling and induced Ki67 expression.
• An anti-Hresistin antibody protected against RV hypertrophy and failure in PH models.

Conclusions:

• Hresistin is expressed in cardiac tissue and contributes to RV dysfunction and maladaptive remodeling in PH.
• Hresistin's immunoregulatory activities are central to its cardiac effects.
• Targeting Hresistin-mediated cardiac inflammation presents a potential therapeutic strategy for PH-associated heart failure.