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Research Units

Heart Failure Research Unit

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Research Outline

Research Related to the Pathogenesis of Heart Failure

In Japan, as in many other western countries, the incidence of cardiovascular diseases continues to show an upward trend accompanying the increase in lifestyle-related diseases and the increase in proportion of the aged population. This increasing trend can be attributed to the aging population and also to the fact that acute-phase deaths have decreased due to recent technological advances and many survived patients subsequently follow a course of chronic heart failure. Therefore elucidation of the mechanisms of chronic heart failure and the development of therapies are absolutely imperative. The development of heart failure is associated with neurohumoral factors including renin-angiotensin, aldosterone and sympathetic activity. It is known that these factors act as exacerbating factors promoting the progression of myocardial hypertrophy and myocardial remodeling, eventually leading to uncompensated myocardial failure. Our unit has demonstrated that oxidative stress plays a very important role in the pathogenetic process of heart failure (see figure below).

Fig. 1: Mitochondrial electron transfer system and electron flow

Dynamic redox reactions occur constantly in the human body, and these reactions are especially prominent in the myocardium that produces large quantities of ATP from oxygen. Inside the cell, the mitochondrial electron transfer system, which is an important site of energy production, is also the major source of reactive oxygen species production utilizing the electric gradient.

When the oxygen concentration increases markedly or when the respiratory chain is blocked such as in pathological situations of inflammation and ischemia-reperfusion, ADP is also lowered and re-oxidized while the electron flow is restricted and leaks easily. As a result, superoxide is produced by Complex I or Complex III. These reactive oxygen species generated from the mitochondrial electron transfer chain play an important role in heart failure. A series of studies conducted in our unit have demonstrated that controlling the generation of these reactive oxygen species leads to the control of myocardial remodeling and that the key to this control is the mitochondrial DNA. Our on-going studies aim at applying these findings to treatment.

  1. Mitochondrial DNA (mtDNA) damage and reactive oxygen species generation in heart failure
  2. Research related to the roles of mitochondrial transcription factor A (TFAM) in heart failure
  3. The mechanisms of anti-remodeling effects by vagal nerve stimulation

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