The effect of Peroxisome Proliferator‐Activated Receptor‐α on NOX‐4 expression in the heart during a slow‐pressor dose of Angiotensin‐II induced hypertension

Aging decreases myocardial peroxisome proliferator activated receptor –alpha (PPAR‐α) expression and activation of PPAR‐α reduces hypertension and cellular oxidative damage. Previous results from our laboratory suggest that PPAR‐α attenuates hypertension and oxidative damage by reducing NOX‐2 expression in the heart during a slow‐pressor dose of Angiotensin II (Ang II). The goal of this project is to determine if PPAR‐α also reduces hypertension and cellular oxidative damage through a NOX‐4 dependent mechanism. We hypothesize that PPAR‐α plays an important role in attenuating the pressor response to Ang II by negatively regulating NOX‐4 expression in the heart. To address this hypothesis, male (48 weeks old) PPAR‐α knockout (KO) mice and wild type (WT) mice were implanted with biotelemetry devices and infused with a slow pressor dose of Ang II (400 ng/kg/min) for 12 days. On day 12 of Ang II, MAP was increased in KO when compared to WT, 167 ± 6 and 145 ± 3 mmHg, respectively. Hearts were homogenized and 25 μg of supernatant proteins were separated by 10% SDS‐PAGE, transferred to nitrocellulose paper, and blotted against antibodies to NOX‐4. The expression of NOX‐4 in the heart was not significantly different between KO and WT controls. NOX‐4 expression was also not different between Ang II‐treated KO (10 ± 10 ODU) and Ang II‐treated WT (12 ± 8 ODU) mice. Despite no differences in NOX‐4 expression in the heart, TBARS, an index of oxidative stress, concentration was increased in PPAR‐α KO + Ang II (12.4 ± 1 μM) when compared to WT + Ang II (10 ± 1 μM). Our results suggest that the differences in the blood pressure response to a slow pressor dose of Ang II between PPAR‐α KO and WT mice are not due to increased NOX‐4 expression in the heart. Previous results from our laboratory suggest that increased NOX‐2 expression in the heart and plasma levels of Interleukin‐17 are mechanisms that may cause a significant increase in the Ang II‐induced slow‐pressor response in PPAR‐α KO mice when compared to WT + Ang II. Future studies are needed to determine if increased NOX‐2 expression alone accounts for the signicant increase in blood pressure and oxidative stress in PPAR‐α KO + Ang II mice. Studies are also needed to determine if increased plasma levels of Interleukin‐17 contributes to the increased blood pressure and oxidative stress in PPAR‐α KO + Ang II mice. Support or Funding Information Howard University Advancing Diversity in Aging Research – National Institute on Aging 1R25AG047843