Key result
Cardiac-specific Hresistin overexpression caused right ventricular dysfunction via HMGB1-mediated inflammation, while an anti-Hresistin human antibody protected the myocardium from hypertrophy and improved survival in rodent models.
Why the study?
It was unclear whether activation of resistin-like molecules can directly cause pulmonary hypertension-associated cardiac dysfunction and remodeling.
Hresistin mediates pulmonary hypertension-associated right ventricular dysfunction through HMGB1-dependent cardiac inflammation, offering a potential novel therapeutic target.
Resistin inhibition protected rodent myocardium from hypertrophy; leaves open translation to human pulmonary hypertension trials.
Background Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin‐like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin‐like molecules can directly cause PH‐associated cardiac dysfunction and remodeling. Methods and Results In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin‐like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac‐specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca 2+ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP‐activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage‐associated molecular pattern molecule high‐mobility group box 1, and subsequently induced pro‐proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti‐Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Conclusions Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH‐associated RV hypertrophy and failure in humans.
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Lin et al. (2023) studied Pulmonary Hypertension with Right Ventricular Dysfunction. Anti-Hresistin human antibody vs. Isotype-matched control IgG1 or vehicle was evaluated on Right ventricular dysfunction and remodeling (assessed by echocardiography, hemodynamics, and histology) (p=<0.05). Cardiac-specific Hresistin overexpression caused right ventricular dysfunction via HMGB1-mediated inflammation, while an anti-Hresistin human antibody protected the myocardium from hypertrophy and improved survival in rodent models.
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