Peroxisome Proliferator-Activated Receptor-γ Regulates Inflammation and Renin-Angiotensin System Activity in the Hypothalamic Paraventricular Nucleus and Ameliorates Peripheral Manifestations of Heart Failure
Activation of peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, has been shown to inhibit the production of proinflammatory cytokines and, in peripheral tissues, to downregulate the renin-angiotensin system. PPAR-γ is expressed in key brain areas involved in cardiovascular and autonomic regulation. We hypothesized that activation of central PPAR-γ would reduce sympathetic excitation and ameliorate peripheral manifestations of heart failure (HF) by inhibiting central inflammation and brain renin-angiotensin system activity. Two weeks after coronary artery ligation, HF rats received an intracerebroventricular infusion of the PPAR-γ agonist pioglitazone or vehicle for another 2 weeks. PPAR-γ expression in the paraventricular nucleus of hypothalamus, an important cardiovascular region, was unchanged in HF compared with sham-operated rats. However, PPAR-γ DNA binding activity was reduced, nuclear factor-κB activity was increased, and expression of proinflammatory cytokines and angiotensin II type-1 receptor was augmented in the HF rats. Mean blood pressure response to ganglionic blockade was greater; plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased; and maximal left ventricular dP/dt was decreased. All of these findings were ameliorated in HF rats treated with intracerebroventricular pioglitazone, which increased PPAR-γ expression and DNA binding activity in the paraventricular nucleus of hypothalamus. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after myocardial infarction can be modulated by activation of PPAR-γ in the brain. Central PPAR-γ may be a novel target for treatment of sympathetic excitation in myocardial infarction–induced HF.
- peroxisome proliferator-activated receptor-γ
- proinflammatory cytokines
- renin-angiotensin system
- nuclear factor-κB
- autonomic regulation
- Received September 4, 2011.
- Revision received September 22, 2011.
- Accepted October 22, 2011.
- © 2011 American Heart Association, Inc.