Peroxisome proliferator-activated receptors-alpha (PPAR-α) and chronic heart failure: Is there a reason to discuss the metabolic strategy of treatment?


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Abstract

Despite improved prognosis in patients with heart failure (HF) treated with neurohumoral activation-suppressing drugs (such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, Β-adrenergic receptor antagonists, aldosterone receptor antagonists), mortality from heart failure remains high, myocardial contractile dysfunction progresses, and the left ventricle becomes enlarged. This leads to the need to elaborate novel approaches to treating HF. The latter is obviously due to impaired myocardial energy substrate metabolism. The mechanisms underlying this phenomenon are numerous and complex. These include reduced myocardial expression and activity of key free fatty acid oxidative enzymes. The expression of these enzymes is controlled by peroxisome proliferator-activated receptors-α (PPAR-α). Thus, PPAR-α activation is a direct method to regulate myocardial fatty acid metabolism. Evidence for the efficiency of therapeutic strategies based on the fact that fatty acid metabolism may be modulated is controversial, which indicates that there may be more complex molecular/biochemical changes than supposed before. The data available in the literature suggest the promises of the above strategy and its serious therapeutic potential.

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α-Рецепторы, активируемые пролифераторами пероксисом (PPAR-α) и хроническая сердечная недостаточность: есть ли повод для обсуждения метаболической стратегии терапии?. - Аннотация. Несмотря на улучшение прогноза у пациентов с сердечной недостаточностью (СН), которые получают терапию, подавляющую нейрогуморальную активацию (ингибиторы ангиотензинпревращающего фермента, антагонисты рецепторов ангиотензина II, Β-адреноблокаторы, антагонисты альдостерона), сохраняется высокая смертность, прогрессируют сократительная дисфункция миокарда и расширение левого желудочка. Это обусловливает необходимость создания новых подходов к лечению. Очевидно, что СН обусловлена нарушением метаболизма энергетических субстратов в миокарде. Механизмы, лежащие в основе этого феномена, многочисленны и сложны, включая снижение экспрессии и активности в миокарде ключевых ферментов окисления свободных жирных кислот. Экспрессия этих ферментов находится под контролем α-рецепторов, активируемых пролифератором пероксисом (PPAR-α). Таким образом, активация PPAR-α является прямым методом регуляции метаболизма жирных кислот в миокарде. Данные об эффективности терапевтических стратегий, основанных на модуляции метаболизма жирных кислот, противоречивы, что указывает на возможность более сложных молекулярных/биохимических изменений, чем предполагалось ранее. Данные литературы свидетельствуют о перспективности указанной стратегии и ее серьезном терапевтическом потенциале.
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