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Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary
Inês Falcão-Pires1, Nádia Gonçalves, Tiago Henriques-Coelho
1Department of Physiology, Cardiovascular R and D Unit, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
Abstract:
We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 microg*kg(-1)*day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 +/- 38%), diameter of cardiomyocyte (40 +/- 10%), myocardial fibrosis (95 +/- 20%), peak systolic pressure (99 +/- 22%), peak rate of ventricular pressure rise (dP/dt(max); 74 +/- 24%), peak rate of ventricular pressure decline (dP/dt(min); 73 +/- 19%), and time constant tau (55 +/- 16%). In these animals, RV expression of apelin (-73 +/- 10%) and its receptor APJ (-61 +/- 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 +/- 713%), angiotensinogen (191 +/- 147%), endothelin-1 (RV, 497 +/- 156%; and LV, 799 +/- 309%), plasmatic levels of apelin (104 +/- 48%), and angiotensin 1-7 (161 +/- 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.
Insights
The apelin-APJ system is crucial in pulmonary hypertension (PH). Chronic administration of pyroglutamylated apelin-13 (Pyr-AP13) attenuated right ventricular hypertrophy and diastolic dysfunction in rats with PH.
Area of Science:
- Cardiovascular Physiology
- Pulmonary Medicine
- Endocrinology
Background:
- Pulmonary hypertension (PH) involves complex cardiovascular and neurohumoral changes.
- The role of the endogenous apelin-APJ system in PH pathophysiology requires further elucidation.
- Monocrotaline (MCT)-induced PH in rats serves as a relevant model for studying PH progression and therapeutic interventions.
Purpose of the Study:
- To investigate the endogenous apelin system's role in MCT-induced PH.
- To evaluate the cardiac and pulmonary effects of chronic pyroglutamylated apelin-13 (Pyr-AP13) administration in this PH model.
Main Methods:
- Male Wistar rats were subjected to MCT injection to induce PH.
- Animals received chronic treatment with Pyr-AP13 or saline.
- Hemodynamic, morphometric, histological, and molecular analyses were performed on cardiac and pulmonary tissues.
Main Results:
- MCT-induced PH led to significant right ventricular (RV) hypertrophy, cardiomyocyte diameter increase, and myocardial fibrosis.
- RV expression of apelin and its receptor APJ was downregulated in MCT-treated rats.
- Pyr-AP13 treatment attenuated RV hypertrophy, normalized cardiac function, and prevented downregulation of the apelin-APJ system.
Conclusions:
- The apelin-APJ system plays a significant role in the pathophysiology of PH.
- Chronic Pyr-AP13 administration demonstrates therapeutic potential by attenuating RV overload and associated neurohumoral activation.
- Targeting the apelin-APJ system offers a promising strategy for managing PH.
