Dipeptidyl Peptidase 4 Inhibition Ameliorates Hypertensive Heart Failure via Suppression of Angiotensin-ii-mediated Cardiac Na plus /h+Exchanger1 Pathway

Introduction: Hypertension is primary cause of heart failure (HF). Several reports demonstrated the blood-pressure (BP)-lowering property of dipeptidyl peptidase 4 (DPP4) inhibitors. Hypothesis: We tested the effect of a new DPP4 inhibitor teneligliptin on BP and HF using preclinical models. Methods: Spontaneously hypertensive rats (SHR; 10 week-old male) and normotensive counterpart (WKY) were treated with TEN (10mg/kg/day) for 4 weeks. Hypertensive HF was evaluated in terms of BP, cardiac function, histological remodeling, and pulmonary congestion. Results: Cardiac catheterization revealed that TEN ameliorated hypertension of SHR-CON (Fig.1). The maximum dP/dt of SHR-CON was elevated (10452±539 for SHR-CON and 5739±599 for WKY-CON), which was reduced by TEN (8033±656 in SHR-TEN) without affecting heart rate. Diastolic indices (minimum dP/dt and tau) were ameliorated by TEN. SHR-CON exhibited increase in heart and body weight (BW) ratio, left ventricular (LV) wall thickness, cardiomyocyte hypertrophy and fibrosis, which were attenuated by TEN. Elevated lung weight and BW ratio and circulating BNP level of SHR-CON were ameliorated by TEN. Cardiac and circulating DPP4 activities of SHR-CON were elevated, which was suppressed by TEN. Vasorelaxant signaling (Akt/eNOS) of each aorta and heart remained unaffected by TEN. Circulating angiotensin-2 (AT-II) was elevated in SHR-CON, which was suppressed by TEN without affecting ACE activity (Fig1). Because DPP4 interacts with Na+/H+ exchanger (NHE)-1 and -3, and NHE1 is related to hypertension and cardiac hypertrophy. In SHR-CON heart, NHE1 expression was elevated (Fig1), which was decreased by TEN. NHE-1 of cultured cardiomyocytes was upregulated by AT-II. Conclusions: TEN ameliorates hypertensive HF via normalizing elevated AT-II through an ACE-independent pathway, leading to reversal of hypertensive cardiac remodeling modulated by pathological AT-II/NHE-1 axis.