Abstract 325: Administration Of Apelin Modulates Myocardial Expression Of Apelin-apj And Improves Right Ventricular Performance In Mct-induced Pulmonary Hypertension

Background: Apelin (AP) is the endogenous vasoactive ligand of APJ receptor. It is widely expressed in the heart and lungs and has important cardiovascular functions such as endothelium-dependent vasodilatation and positive inotropic effect. However, the role of apelin-APJ system in pulmonary hypertension (PH) remains to be clarified. Objective: To evaluate the chronic effects of apelin in: right ventricular (RV) myocardial function; cardiac expression of apelin and APJ in healthy and MCT-PH rats Methods: Male Wistar rats were randomly injected with MCT (60mg/Kg, sc) or vehicle (CTR, day 0). One week later, half of these animals were randomly treated with Pyr-apelin-13 (200μg/Kg/day, ip) or a similar volume of vehicle. The study resulted in 4 groups: CTR; AP; MCT and MCT+ AP. At day 24, animals were instrumented to record RV peak systolic (Pmax) pressures, dP/dtmax, dP/dtmin and time constant Tau. Also, heart and lungs were weighted and transmural RV samples were collected for relative quantification of mRNA by real-time RT-PCR. Results are on table . Conclusions: In healthy rats, exogenous apelin potentiates its endogenous production with no significant changes in APJ. MCT-induced PH resulted in a significant down-regulation of apelin-APJ system, which might play a role in the systolic and diastolic dysfunction observed in this model. This down-regulation was completely reverted by chronic administration of exogenous apelin. Therefore, apelin upregulates the cardiac apelin-APJ system exerting beneficial effects on cardiac remodeling and function, namely, by decreasing PH, RV diastolic function and hypertrophy. These results reveal the importance of apelin-APJ system in the pathophysiology of PH, suggesting that apelin is a potential therapeutic target in this disease. Results table

Download Full-text

Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00089.2009 ◽

2009 ◽

Vol 296 (6) ◽

pp. H2007-H2014 ◽

Cited By ~ 99

Author(s):

Inês Falcão-Pires ◽

Nádia Gonçalves ◽

Tiago Henriques-Coelho ◽

Daniel Moreira-Gonçalves ◽

Roberto Roncon-Albuquerque ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Systolic Pressure ◽

Pressure Rise ◽

Chronic Administration ◽

Left Ventricular ◽

Ventricular Pressure ◽

Peak Rate ◽

Male Wistar Rats ◽

Neurohumoral Activation

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 μg·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/d tmax; 74 ± 24%), peak rate of ventricular pressure decline (dP/d tmin; 73 ± 19%), and time constant τ (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.

Download Full-text

Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00480.2005 ◽

2006 ◽

Vol 291 (5) ◽

pp. L912-L922 ◽

Cited By ~ 65

Author(s):

Crystal Kantores ◽

Patrick J. McNamara ◽

Lilian Teixeira ◽

Doreen Engelberts ◽

Prashanth Murthy ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Antioxidant Properties ◽

Ventricular Performance ◽

Pulmonary Vascular Remodeling ◽

Beneficial Effects ◽

Arterial Resistance ◽

Pulmonary Arterial

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals ( P < 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway.

Download Full-text