トレーニングによるAT受容体経路の不活性化は、高血圧ラットの高血圧前から高血圧期への移行期に自律神経制御と心臓のリモデリングを促進する

Training-Induced Deactivation of the AT Receptor Pathway Drives Autonomic Control and Heart Remodeling During the Transition From the Pre- to Hypertensive Phase in Spontaneously Hypertensive Rats.

• Tassia Santos Rodrigues da Costa
• Gustavo Santos Masson
• Rosangela Aparecida Dos Santos Eichler
• Juliane Cristina de Souza Silva
• Silvia Lacchini
• Lisete Compagno Michelini

抄録

背景:

高血圧と運動訓練（T）が、高血圧発症時のレニン-アンジオテンシン系（RAS）、自律神経制御、心臓リモデリングの相互作用に及ぼす影響を評価した。また、血行動態の記録は、意識下での血行動態の記録である。血行動態の記録は、実験週0,1,2,4,8で意識のあるラットで行った。左心室（LV）を採取し、RAS遺伝子とタンパク質の発現、心筋細胞の肥大とコラーゲンの蓄積を評価した。降圧前のSHRはATR遺伝子発現の増強を示した；5週目には血圧上昇、LVアンギオテンシノーゲンとACE mRNA発現の増加、その後交感神経興奮を呈した（8週目以降）。また、12週齢の鎮静型SHRでは、顕著なATRタンパク質含量、筋細胞の肥大、コラーゲン沈着、血圧変動の増加が観察された。これらすべての効果を減衰させることに加えて、T活性化されたMas受容体の発現は心臓の副交感神経の変調を増強し、発症を遅らせ、その大きさを減少させたが、遺伝性高血圧の発症をブロックすることはなかった。

BACKGROUND: The effects of hypertension and exercise training (T) on the sequential interplay between renin-angiotensin system (RAS), autonomic control and heart remodeling during the development of hypertension in spontaneously hypertensive rats (SHR), was evaluated.Methods and Results:Time course changes of these parameters were recorded in 4-week-old SHR submitted to a T or sedentary (S) protocol. Wistar Kyoto rats served as controls. Hemodynamic recordings were obtained in conscious rats at experimental weeks 0, 1, 2, 4, and 8. The left ventricle (LV) was collected to evaluate RAS gene and protein expression, cardiomyocytes' hypertrophy and collagen accumulation. Pre-hypertensive SHR exhibited augmented ATR gene expression; at 5 weeks, they presented with elevated pressure, increased LV angiotensinogen and ACE mRNA expression, followed by sympathoexcitation (from the 8week onwards). Marked ATR protein content, myocytes's hypertrophy, collagen deposition and increased pressure variability were observed in 12-week-old sedentary SHR. In addition to attenuating all these effects, T activated Mas receptor expression augmented parasympathetic modulation of the heart, and delayed the onset and reduced the magnitude, but did not block the development of genetic hypertension.

結論:

高血圧発症時と運動訓練中のLV ACE-Ang II-ATR軸の変化、自律神経制御、心筋リモデリングとの間に密接な時間的関係があることから、高血圧発症前から運動訓練中への移行期における心筋リモデリングと自律神経調節の推進にATR経路が果たす本質的な役割が明らかになった。

CONCLUSIONS: The close temporal relationship between changes in the LV ACE-Ang II-ATR axis, autonomic control and cardiac remodeling at both the establishment of hypertension and during exercise training reveals the essential role played by the ATR pathway in driving cardiac remodeling and autonomic modulation during the transition from the pre- to hypertensive phase.