SY 05-2 PROGRESSION OF HYPERTENSIVE HEART DISEASE: NEW THERAPEUTIC APPROACH

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Abstract

Hypertensive patients have greater chances of such cardiovascular events as stroke, coronary heart disease, heart or renal failure, peripheral artery disease, and dementia. It is also well recognized that diabetes increases the cardiovascular risks in concert with hypertension. Therefore, main goals for an innovation of anti-hypertensive therapy would be to achieve further risk reduction by targeting the functional, metabolic, and structural alterations associated with hypertension. Professors Dzau and Braunwald et al proposed the concept of “the cardiovascular disease continuum” in 1991, and that hypertension may trigger the chain of events, leading to end-stage heart disease; however, this concept was quite new at that time, and there was some discussion whether “the cardiovascular disease continuum” is true or not. Fifteen years later, accumulating clinical and basic research evidence confirmed the validity of the concept of this cardiovascular disease continuum. Oxidative stress, and inflammation play a role in the initiation and continuation of this chain. Therefore, targeting oxidative stress and inflammation are important to interrupt the cardiovascular disease continuum. However, so far, neither anti-oxidative nor anti-inflammation strategy can work well to prevent hypertension and its related cardiovascular diseases. Low-grade inflammation has been proposed to play a key role in the pathogenesis of hypertension, and both innate and adaptive immune responses may participate in this process. Recent evidence also defined important roles of T-cell and T-cell-derived cytokines associated with angiotensin (Ang) II and catecholamine. We expect these new findings could provide us with novel avenues to beat hypertension, in terms of anti-oxidative stress and/or anti-inflammation.

Renin-angiotensin-aldosterone system (RAAS) plays a significant role in the cardiovascular disease continuum interacting with adrenergic system and other various mediators, and thereby RAAS mediates adaptive and maladaptive responses to tissue injury. Sympathetic hyperactivity and the activation of RAAS may promote hypertension or work as an amplifier of the pressor influence of other factors such as metabolic factors. Therefore, RAAS and sympathetic nervous system are the major targets of treatment of hypertension and its related cardiovascular complications. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, have been used in clinical practice for treatment of resistant hypertension and the renal denervation is also being evaluated for treatment of various comorbidities, although the efficacy of invasive sympatho-deactivating interventions have not yet been conclusively validated. In the past two decades, the development of the drugs for the treatment of hypertension and cardiovascular diseases has been largely focused on the inhibitors of RAAS, including immunization against Ang II.

Novel pathways beyond the classical actions of RAAS, the angiotensin converting enzyme (ACE)/Ang II/Ang II type 1 (AT1) receptor axis, have been highlighted: the ACE2/Ang-(1–7)/Mas receptor axis and Ang II type 2 (AT2) receptor as a new opposing axis against the classical RAS axis as a protective arm of RAAS. Moreover, identification of alamandine and its receptor, Mas-related G-protein coupled receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS. Further elucidation of the regulatory mechanisms of the functions of new protective arm of RAS beyond the classical RAAS could provide us with possibilities for the development of novel drugs that regulate RAAS in a more sophisticated manner, thereby treating hypertensive patients and achieving cardiovascular risk reduction more efficiently. Agonists of protective arm of RAS have been developed as new drugs for hypertension and several drugs of the agonists of protective arm of RAS are now in clinical trials. Several novel Ang II receptor interacting proteins have been also reported. AT1 receptor-associated protein (ATRAP) was cloned by us as specific binding protein of AT1 receptor C-terminal, and we and others reported that ATRAP could act as a negative regulator in AT1 receptor-mediated effects at least in part by the enhancement of AT1 receptor internalization. We cloned AT2 receptor interacting protein (ATIP) as a protein interacting specifically with the C-terminal tail of the AT2 receptor. We and others demonstrated that ATIP enhanced an important role of AT2 receptor-mediated wide variety of pathophysiological functions. Further elucidation of the functional regulation of these Ang II receptor associated proteins including their transcriptional control, and finding possible ligands could be helpful for new drug developments.

I will review and discuss in this symposium “Progression of Hypertensive Heart Disease” focusing on the new therapeutic pharmacological approach with recent clinical evidences.

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