# Ac-SDKP in the Treatment of Cardiac Dysfunction in Hypertension or Ischemic Heart

> **NIH NIH R01** · HENRY FORD HEALTH SYSTEM · 2020 · $463,734

## Abstract

Hypertension is a major health care burden in the United States, affecting 1 in 3 adults. Hypertension is
associated with concomitant coronary artery disease with myocardial infarction (MI) and heart failure (HF). In
this study, we will define how N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) protects cardiac structure and
function in a mouse model of HF that will be induced in two models [angiotensin II (Ang II) hypertension- or
permanent left anterior descending coronary ligation (LAD)]. We and others reported that Ang II-induced
hypertension or LAD resulted in HF associated with cardiac structural remodeling and impaired function. Ac-
SDKP is successively produced from thymosin 4 (T4) by two enzymes, meprin  and prolyl oligopeptidase
(POP). Circulating and tissue Ac-SDKP depends on the angiotensin converting enzyme (ACE) activity, since Ac-
SDKP is mainly degraded by the N-terminal active side of ACE (ACE-N). ACEi are first-line drugs to treat HF.
ACEi have strong side effects such as hypotension, cough, rash, angioneurotic edema, hyperkalemia, and
dysgeusia, whereas Ac-SDKP has none, even at high dosages (up to 48 mg/kg/d). Also, Ac-SDKP is down-
regulated in the myocardium of dogs and patients with chronic HF. Whether and how Ac-SDKP therapy could
rescue hypertension- or LAD-induced cardiac complications remain to be elucidated. Increasing circulating Ac-
SDKP not only inhibited fibrosis and mediators of inflammatory cell infiltration into the injured myocardium, but it
also improved cardiac function in mice with LAD or hypertension (preliminary data). We have found that Ac-
SDKP inhibits endoplasmic reticulum (ER) stress in cardiac fibroblasts in vitro and in mice with MI and restores
phosphor-AKT in hypertensive hearts. Activation of ER stress is detrimental to the endothelium, cardiac
fibroblasts, and cardiomyocytes. These findings set the scientific premise of this work, providing foundational
work that Ac-SDKP represents a beneficial supplement to the existing cardiac pharmacotherapy. Our central
hypothesis is that Ac-SDKP protects and potentiates cardiac protection against heart failure via the
inhibition of ER stress. We propose to use the mouse model of heart failure induced by hypertension or LAD
to address the following 2 two aims: (
1)
we will determine whether Ac-SDKP protects the heart and provides
additional cardiac protective effects to ARBs, ACEi, or eplerenone in mice with MI or hypertension, (
2)
and we
will demonstrate that Ac-SDKP improves cardiac function in mice with hypertension or LAD by inhibiting the
detrimental ER stress via the PI3K/AKT pathway. A number of conditional and tissue-specific knockout female
and male mice will be employed. A team with significant expertise is recruited for this project, which will apply a
combination of state-of-the-art in vivo, cell and molecular techniques including measurements of cardiac
remodeling and function by echocardiography in non-anesthetized mice and radiotelemetry, ...

## Key facts

- **NIH application ID:** 9987732
- **Project number:** 5R01HL136456-03
- **Recipient organization:** HENRY FORD HEALTH SYSTEM
- **Principal Investigator:** NOUR-EDDINE RHALEB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,734
- **Award type:** 5
- **Project period:** 2018-09-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987732

## Citation

> US National Institutes of Health, RePORTER application 9987732, Ac-SDKP in the Treatment of Cardiac Dysfunction in Hypertension or Ischemic Heart (5R01HL136456-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987732. Licensed CC0.

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